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Exercise and muscle dysfunction in COPD: Implications for pulmonary rehabilitation
Abstract
Skeletal muscle dysfunction in COPD (chronic obstructive pulmonary disease) patients, particularly of the quadriceps, is of clinical interest because it not only influences the symptoms that limit exercise, but may also contribute directly to poor exercise performance and health status, increased healthcare utilization, and mortality. Furthermore, unlike the largely irreversible impairment of the COPD lung, skeletal muscles represent a potential site to improve patients' level of function and quality of life. However, despite expanding knowledge of potential contributing factors and greater understanding of molecular mechanisms of muscle wasting, only one intervention has been shown to be effective in reversing COPD muscle dysfunction, namely exercise training. Pulmonary rehabilitation, an intervention based on individually tailored exercise training, has emerged as arguably the most effective non-pharmacological intervention in improving exercise capacity and health status in COPD patients. The present review describes the effects of chronic exercise training on skeletal muscles and, in particular, focuses on the known effects of pulmonary rehabilitation on the quadriceps muscle in COPD. We also describe the current methods to augment the effects of pulmonary rehabilitation and speculate how greater knowledge of the molecular pathways of skeletal muscle wasting may aid the development of novel pharmaceutical agents.
... O aumento da expectativa de vida associado a fatores ambientais ou sociais e o consequente envelhecimento da população produz o aumento da incidência da Doença Pulmonar Obstrutiva Crônica (DPOC) [1]. No Brasil são 46.311.580 ...
... A redução da capacidade física em indivíduos portadores de DPOC é causada por uma sinergia de fatores associados diretamente ao envelhecimento [1]. Entre eles a baixa capacidade oxidativa celular, dispnéia, hiperinsufl ação dinâmica, baixa tolerância a esforços, hipoxemia, anemia e redução da força muscular associada à inatividade [1,[4][5][6]13]. ...
... A redução da capacidade física em indivíduos portadores de DPOC é causada por uma sinergia de fatores associados diretamente ao envelhecimento [1]. Entre eles a baixa capacidade oxidativa celular, dispnéia, hiperinsufl ação dinâmica, baixa tolerância a esforços, hipoxemia, anemia e redução da força muscular associada à inatividade [1,[4][5][6]13]. ...
Introdução: A Doença Pulmonar Obstrutiva Crônica (DPOC) é um dos focos dos projetos de saúde pública cursando com alta incidência e prevalência em adultos e idosos. A abordagem terapêutica a DPOC compreende o entendimento das vias moleculares de inflação, degradação proteica e hipertrofia. Objetivo: Discutir as vias de sinalização para hipotrofia/hipertrofia adjuntas as diferentes suplementações para o paciente com DPOC compensada. Método: Foram cotejados e analisados artigos publicados em revistas presentes na base de dados da PubMed, utilizando-se palavras em inglês como: amino acids supplementation, COPD, hypertrophy pulmonary rehabilitation em diferentes combinações, mas sempre com a palavra COPD presente. Resultados: O exercício é um estressor metabólico que aumenta a mobilização de aminoácidos e a inflamação local e aguda com sinalização para síntese proteica. Diferentes peptídeos de produção rápida estão envolvidos neste mecanismo com modulação no status muscular, sendo a intensidade e a velocidade de execução do exercício os principais mediadores do processo. A suplementação nutricional e hormonal associadas a um programa de exercícios são estratégias que aumentam a força e resistência muscular e reduzem o risco de internação e êxito letal. Conclusão: O exercício é uma intervenção não farmacológica efetiva no tratamento de pacientes com doença metabólica subsequente a DPOC. A utilização de fármacos e suplementos nutricionais é factível na terapêutica cotidiana do profissional de saúde com a finalidade de aumentar massa magra e resistência física.Palavras–chave: caquexia, suplementação, aminoácidos, hipertrofia, catabolismo, reabilitação.
... Higher intensity means better results in COPD patients. 11,18,19 Seventy-five percent of 6MWT velocity intensity was applied by Probst et al. 10 in treadmill exercise, 60% maximum work load velocity of static ergocycle exercise, stepup-and-down stairs exercise and strengthening upper and lower extremities exercise with 70% of one repetition maximum (1RM) in moderate to severe stage COPD. These training which was done for 1.5 hours each session, 3 times per week for 12 weeks resulted in lower increase of walking distance (44 m) compared to our study which reasoned with higher intensity given (80 %) even though only for a shorter duration of aerobic exercise (30-60 minutes) for 6 weeks. ...
... Preference of shorter duration was based on several studies that describe aerobic training in COPD pulmonary rehabilitation will give good adaptational muscle change when duration of the exercise is between 30-50 minutes, 3-5 times/week for 5-10 weeks. 18,19 Skeletal muscle dysfunction in COPD especially is caused by inactivity from shortness of breath during activities that reason for inactivity and deconditioning cycle and in the end causes bigger muscle impairment even to low intensity activity. 3,4,11 Inactivity causes structural and biochemistry changes in muscles such as decreased proportion of type I muscle fiber; changes of type IIa to II b muscle fibers; decreased oxydative enzyme, number and density of mitochondrias; along with decreased muscle capillaries. ...
... 17 Therefore, aerobic exercise in moderate stage COPD is focused on lower extremity muscles' endurance exercise with the preferred treadmill method since this will better induce increased muscle endurance for daily activities. Adapted changes in muscle happen due to proliferation of capilary to the muscle, increased proportion of type I muscle fiber, changes from type II b to II a muscle fiber happened frequently, increased number and size of mitochondria in trained muscle group and increased oxydative enzyme responsible for oxydative phosphoric process (citrate sintethase/CS and 3-hydroxyl CoA dehidrogenase/HADH). 10,18 Overcoming muscle dysfunction problem in COPD, high intensity of exercise is needed in increasing skeletal muscle aerobic capacity in the aim of increasing exercise capacity and reducing the event of shortness of breath in submaximal work load. [17][18][19] In COPD, exercise intensity is preferred the highest tolerated intensity and maintained for minimal 20 minutes. ...
Skeletal muscle dysfunction poses as one of the systemic manifestation of chronic obstructive pulmonary disease (COPD) in the impact of inactivity and deconditioning from early fatigue to the end of declining quality of life (QoL). Giving pulmonary rehabilitation program of treadmill exercise will overcome the problem, but standard method for moderate stage of COPD is not yet available. This study aimed to evaluate the effect of treadmill exercise using 80% intensity of six minute walk test on walking distance and QoL in moderate stage COPD in order to overcome muscle dysfunction. Samples were taken from Physical Medicine and Rehabilitation and Respirology subdivision of Internal Medicine outpatient clinic of Dr. Hasan Sadikin General Hospital Bandung, from March 2012–April 2013. Data analysis was tested using t-test for comparison of two independent mean data. Otherwise, non parametric test of Mann Whitney and Wilcoxon Match Pair test. Thirty three subjects of moderate stage COPD were divided into 2 groups (intervention and control). Intervention group received treadmill exercise with 80% intensity from preliminary 6MWT for 30–60 minutes/session, 3 session/week for 6 weeks. Significant increase on walking distance was found in intervention group (70.66 m) compared to control group (7.43 m) after 6 weeks (p≤0.05). QoL using St. George Respiratory Questionnaire (SGRQ) showed significant decrease in intervention group for all components in the end of 6 weeks (total p=0.0038, symptoms p=0.0162, activities p=0.0043 and impact p=0.0057, p≤0.05). Eighty percent intensity of 6MWT in treadmill exercise for 6 weeks was well tolerated and could overcome skeletal muscle dysfunction in moderate stage COPD. It also revealed higher values in aerobic capacity and QoL compared to previous studies. In conclusion, treadmill exercise using 80% intensity of 6MWT provides further walking distance and higher QoL compared to control in moderate stage COPD.
... Thus, a major contributing factor to the high PAP is the high PVR which results from a variety of factors, including hypoxia-induced vasoconstriction, co-existing LV diastolic dysfunction, remodeling of the vascular bed, altered gas exchange, biomechanical abnormalities (e.g., hyperinflation and heightened intra-thoracic pressures) and musculoskeletal abnormalities. 10, [50][51][52][53] In addition to these factors, the role of mitochondrial dysfunction and alterations in arterio-venous oxygen difference, both of which negatively impact peripheral O 2 uptake, further contribute to exercise limitations. 54 The disease process causes significant exercise limitation due to reductions in forced expiratory volume in one second (FEV 1 ) and tidal volume, in addition to an increase in end expiratory lung volume during exercise resulting in dynamic hyperinflation. ...
... In addition, the significant contribution from the peripheral muscles and diaphragm as a result of the central disease process cannot be underestimated. 51 Along with abnormalities in P ET CO 2 , the change in this, i.e., " P ET CO 2 from rest to AT, has also been shown to have importance in identifying individuals with pulmonary vasculopathy. 56,57 In addition, VE/VCO2@AT is another parameter which is very closely related to the presence of PH, especially in patients with ILD. ...
... 58 In addition to these abnormalities, both these groups of patients also present with peripheral muscle dysfunction including diminished muscle strength, atrophy, mitochondrial dysfunction, poor oxidative capacity and a shift in muscle fiber types (type II to type I). 49,51,52 Changes in diaphragm structure and function further contributes to the respiratory changes seen in both obstructive and restrictive lung diseases. In obstructive diseases, there is a change in position of the diaphragm adversely affects respiratory muscle strength and exercise tolerance. ...
Introduction:
Exercise intolerance in pulmonary hypertension (PH) is a major factor affecting activities of daily living and quality of life. Evaluation strategies (i.e., non-invasive and invasive tests) are integral to providing a comprehensive assessment of clinical and functional status. Despite a growing body of literature on the clinical consequences of PH, there are limited studies discussing the contribution of various physiological systems to exercise intolerance in this patient population. Areas covered: This review, through a search of various databases, describes the physiological basis for exercise intolerance across the various PH etiologies, highlights the various exercise evaluation methods and discusses the rationale for exercise training amongst those diagnosed with PH. Expert commentary: With the growing importance of evaluating exercise capacity in PH (class 1, Level C recommendation), understanding why exercise performance is altered in PH is crucial. Thus, the further study is required for better quality evidence in this area.
... Peripheral muscle weakness may also contribute directly to poor exercise performance. 6,7 Exercise intolerance is often exacerbated by age-related decline in function, physical deconditioning, mood disturbance, lack of motivation, and the presence of comorbidity (Fig. 1). ...
... Usual gait speed measured over 4 m is an established marker of exercise capacity in the elderly, 7 and was recently cited as the most appropriate functional test for interventional trials in frail older adults. 9 The 4-meter gait speed (4MGS) requires patients to walk at their normal walking speed with or without walking aids along a flat, unobstructed 4 m course. ...
Exercise intolerance is a common symptom in chronic obstructive pulmonary disease (COPD), and reflects not only cardiorespiratory status, but global disease severity and prognosis. Evaluating exercise capacity allows the monitoring of disease trajectory and response to intervention. Although formal cardiopulmonary metabolic exercise testing provides a wealth of physiological information, this is impractical in some settings. Field tests, which do not require specialist equipment and expertise, are widely used as surrogates. This review examines established and emerging field tests of exercise capacity, and examines the evidence supporting the validity, reliability, and interpretation of these tests in the assessment of individuals with COPD. The 6-minute walk, incremental shuttle walk, and endurance shuttle walk tests have well-established psychometric properties in COPD. Nonetheless, issues with the time and space required to perform these tests prevent widespread implementation across all health care settings. A range of simpler and shorter functional tests are emerging in COPD, which are suited to most clinical settings including the bedside. These include the 4-meter gait speed, sit-to-stand tests, the Short Physical Performance Battery, and the Stair Climb Power Test. Data on the psychometric properties of these emerging tests are variable in COPD populations and are currently strongest for the 4-meter gait speed and 5-sit-to-stand test. In summary, exercise capacity is an important outcome measure in COPD. There are several well-established and validated field walking tests that reflect exercise capacity. Simpler tests are emerging, which will allow the routine measurement of exercise capacity at the bedside or in home settings.
... Although we cannot close the debate, we can expose some of the main positions. Against the hypothesis of a disease-specific myopathy are the following: (1) many functional and cellular findings in COPD are identical to those of disuse; (2) limb muscle is trainable, because training has been shown to improve muscle strength and endurance, oxidative enzyme activities, fiber cross-sectional area, and muscle capillarization, at least in some patients (307,310); (3) in a small study, highintensity aerobic interval training was shown to restore work performance and oxidative capacity of the quadriceps to a level similar to that found in sedentary individuals (312); and (4) the fact that full recovery of muscle function is unusual does not necessarily indicate a myopathy, because the duration of the training program may be too short to normalize alterations that have developed over several decades (313,314), or early ventilatory limitation may compromise the ability to tolerate sufficient muscle stimulus to improve global or cellular function (311). ...
... Rehabilitative exercise training improves limb muscle function and morphology in patients with COPD (313,314,(496)(497)(498). As such, quadriceps muscle strength, endurance, and fatigability all improve significantly after exercise training (265,314,(496)(497)(498)(499), with smaller, albeit significant, increases in midthigh muscle cross-sectional area (466) and FFM (497). ...
Background:
Limb muscle dysfunction is prevalent in chronic obstructive pulmonary disease (COPD) and it has important clinical implications, such as reduced exercise tolerance, quality of life, and even survival. Since the previous American Thoracic Society/European Respiratory Society (ATS/ERS) statement on limb muscle dysfunction, important progress has been made on the characterization of this problem and on our understanding of its pathophysiology and clinical implications.
Purpose:
The purpose of this document is to update the 1999 ATS/ERS statement on limb muscle dysfunction in COPD.
Methods:
An interdisciplinary committee of experts from the ATS and ERS Pulmonary Rehabilitation and Clinical Problems assemblies determined that the scope of this document should be limited to limb muscles. Committee members conducted focused reviews of the literature on several topics. A librarian also performed a literature search. An ATS methodologist provided advice to the committee, ensuring that the methodological approach was consistent with ATS standards.
Results:
We identified important advances in our understanding of the extent and nature of the structural alterations in limb muscles in patients with COPD. Since the last update, landmark studies were published on the mechanisms of development of limb muscle dysfunction in COPD and on the treatment of this condition. We now have a better understanding of the clinical implications of limb muscle dysfunction. Although exercise training is the most potent intervention to address this condition, other therapies, such as neuromuscular electrical stimulation, are emerging. Assessment of limb muscle function can identify patients who are at increased risk of poor clinical outcomes, such as exercise intolerance and premature mortality.
Conclusions:
Limb muscle dysfunction is a key systemic consequence of COPD. However, there are still important gaps in our knowledge about the mechanisms of development of this problem. Strategies for early detection and specific treatments for this condition are also needed.
... Pulmonary rehabilitation is an intervention based on individually tailored exercise training and aims on improving exercise capacity and health status in COPD patients. In addition to improving endurance and fatigability, exercise training increases muscle strength, muscle mass, and muscle fiber size (Man et al., 2009). Although these effects of exercise training suggest a causal involvement of physical inactivity and disuse in muscle wasting, exercise training does not fully reverse all of the abnormalities observed in the peripheral muscle in COPD (Man et al., 2009). ...
... In addition to improving endurance and fatigability, exercise training increases muscle strength, muscle mass, and muscle fiber size (Man et al., 2009). Although these effects of exercise training suggest a causal involvement of physical inactivity and disuse in muscle wasting, exercise training does not fully reverse all of the abnormalities observed in the peripheral muscle in COPD (Man et al., 2009). In cachectic COPD patients, exercise training-induced increases in myofiber size and muscle IGF-1 expression were significantly attenuated compared to non-cachectic COPD patients, which was accompanied by respectively down-regulation of myostatin and an induction of MyoD expression, only in non-cachectic patients (Vogiatzis et al., 2010). ...
Skeletal muscle wasting contributes to impaired exercise capacity, reduced health-related quality of life and is an independent determinant of mortality in chronic obstructive pulmonary disease. An imbalance between protein synthesis and myogenesis on one hand, and muscle proteolysis and apoptosis on the other, has been proposed to underlie muscle wasting in this disease. In this review, the current understanding of the state and regulation of these processes governing muscle mass in this condition is presented. In addition, a conceptual mode of action of disease-related determinants of muscle wasting including disuse, hypoxemia, malnutrition, inflammation and glucocorticoids is provided by overlaying the available associative clinical data with causal evidence, mostly derived from experimental models. Significant progression has been made in understanding and managing muscle wasting in chronic obstructive pulmonary disease. Further examination of the time course of muscle wasting and specific disease phenotypes, as well as the application of systems biology and omics approaches in future research will allow the development of tailored strategies to prevent or reverse muscle wasting in chronic obstructive pulmonary disease.
... Indeed, the increased knowledge regarding COPD muscle weakness pathophysiology highlights the existence of two main components implicated in lower voluntary force production: intrinsic muscle qualities [43][44][45][46] and impaired central motor command [47,48]. Unfortunately, the muscle-strengthening programs used in PR do not sufficiently take into account this updated knowledge. ...
Pulmonary rehabilitation (PR) in patients with COPD improves quality of life, dyspnea, and exercise tolerance. However, 30 to 50% of patients are “non-responders” (NRs) according to considered variables. Surprisingly, peripheral muscle force is never taken into account to attest the efficacy of PR, despite its major importance. Thus, we aimed to estimate the prevalence of force in NRs, their characteristics, and predictors of non-response. In total, 62 COPD patients were included in this retrospective study (May 2019 to December 2020). They underwent inpatient PR, and their quadriceps isometric maximal force (QMVC) was assessed. The PR program followed international guidelines. Patients with a QMVC increase <7.5 N·m were classified as an NR. COPD patients showed a mean improvement in QMVC after PR (10.08 ± 12.97 N·m; p < 0.001). However, 50% of patients were NRs. NRs had lower pre-PR values for body mass, height, body mass index, PaO2, and QMVC. Non-response can be predicted by low QMVC, high PaCO2, and gender (when male). This model has a sensitivity of 74% and specificity of 81%. The study highlights the considerable number of NRs and potential risk factors for non-response. To systematize the effects, it may be interesting to implement blood gas correction and/or optimize the programs to enhance peripheral and central effects.
... There is still a strong debate on which mode of exercise could be most effective in improving the long-term outcomes in COPD patients. It appears clear that resistance training can reduce sarcopenia and promote muscle fibre hypertrophy [92]. High-intensity exercise could also be beneficial for COPD patients, but in patients with severe disease dyspnoea sensation may limit the amount of sufficiently extended periods of high intensity training [93]. ...
Chronic Obstructive Pulmonary Disease (COPD) is a disease that is spreading worldwide and is responsible for a huge number of deaths annually. It is characterized by progressive and often irreversible airflow obstruction, with a heterogeneous clinical manifestation based on disease severity. Along with pulmonary impairment, COPD patients display different grades of malnutrition that can be linked to a worsening of respiratory function and to a negative prognosis. Nutritional impairment seems to be related to a reduced exercise tolerance and to dyspnoea becoming a major determinant in patient-perceived quality of life. Many strategies have been proposed to limit the effects of malnutrition on disease progression, but there are still limited data available to determine which of them is the best option to manage COPD patients. The purpose of this review is to highlight the main aspects of COPD-related malnutrition and to underline the importance of poor nutritional state on muscle energetics, exercise tolerance and dyspnoea.
... Additionally, exercise training promotes morphological changes such as the transformation of fatigable fast-twitch type II muscle fibers to fatigue-resistant slow-twitch type I fibers (DOURADO et al., 2006;MAN et al., 2009). Another point to consider about interval exercise training is the increase in the muscle cross-sectional area in COPD patients (VOGIATZIS et al ., 2005). ...
The clinical consequences of chronic obstructive pulmonary disease (COPD) include fatigue, dyspnea and progressive impairment of exercise capacity. It also produces significant systemic consequences such as nutritional depletion, physical deconditioning, systemic inflammation, and structural and functional changes in the respiratory and locomotor muscles. Regular exercise provides improvements in the health of patients with stable COPD and can relieve the symptoms, increasing the exercise capacity and improving the quality of life, while also reducing hospitalization and, to some extent, the risk of morbidity and mortality. Training with progressive exercises is associated with metabolic and neurohumoral adaptations, heart rate variability, with adaptations in the pulmonary and skeletal muscles, as well as the inflammatory, cardiovascular and respiratory systems. This review will focus on current knowledge of the mechanisms by which physical training can provide beneficial effects in COPD patients. Results: After analyzing the titles, abstracts and content, out of 500 articles found, 489 were excluded, leaving 11 articles. Studies have shown the beneficial effect of aerobic training on COPD. Conclusion: Physical training should be considered a therapeutic option in patients with COPD, regardless of being terrestrial or aquatic, as it can have beneficial effects on the systems.
... Indeed, the increased knowledge regarding COPD muscle weakness pathophysiology highlights the existence of two main components implicated in lower voluntary force production: intrinsic muscle qualities [43][44][45][46] and impaired central motor command [47,48]. Unfortunately, the muscle-strengthening programs used in PR do not sufficiently take into account this updated knowledge. ...
... Patients with COPD show an impaired exercise tolerance, often with severe dyspnea, a decreased ability to participate in the activities of daily living, and a poor health-related quality of life (HRQoL; Vestbo et al., 2013). Exercise is limited by a combination of impaired ventilatory function (Agusti et al., 2003) and skeletal muscle dysfunction (Man et al., 2009), with weakness of the lower limbs (Maltais et al., 2000) and impaired balance (Roig et al., 2011). The common practice of those observing Ramadan is to have two meals per day: a large meal shortly after sunset and a much lighter one immediately before dawn. ...
This study aimed to carry out a Ramadan observance (RO) on anthropometric, psychosocial, physiological, and postural characteristics of patients with chronic obstructive pulmonary disease (COPD). Twenty COPD patients were evaluated. Tests performed 1 week before Ramadan (C), and during the second (R-2) and the fourth weeks of Ramadan (R-4) included standard anthropometry, spirometry, a quality of life questionnaire (VQ11), a 6-minute walking test (6MWT), measurement of maximal voluntary contraction force of the quadriceps (MVC), Timed Get Up and Go (TUG), Berg Balance Scale (BBS), and Unipedal Stance (UST). During R-2, there were significant decreases in forced vital capacity and forced expiratory volumes, 6MWT distance, MVC, BBS, and UST, with significant increases in TUG and significant changes in VQ11. During R-4, there was some recovery, but all variables remained significantly different from initial control data. To conclude, RO adversely affects pulmonary function, exercise performance, postural balance, and quality of life in COPD, with some recovery by the R-4. Although a number of functional consequences remain to be elucidated, functional losses were insufficient to limit daily living in our sample, but further studies are recommended in those with more severe COPD, paying particular attention to postural disturbances and a possible increase in the risk of falls.
... Muscle weakness negatively impacts functional status and quality of life. [147][148][149] NMES has been demonstrated to result in substantial improvements in peak VO 2 139,141 ,143 ,150 and 6MWT [139][140][141][142][143]150 compared to controls with effect sizes similar to those found with other exercise-based interventions. ...
The American Physical Therapy Association (APTA), in conjunction with the Cardiovascular and Pulmonary Section of APTA, have commissioned the development of this clinical practice guideline to assist physical therapists in their clinical decision making when managing patients with heart failure. Physical therapists treat patients with varying degrees of impairments and limitations in activity and participation associated with heart failure pathology across the continuum of care. This document will guide physical therapist practice in the examination and treatment of patients with a known diagnosis of heart failure. The development of this clinical practice guideline followed a structured process and resulted in 9 key action statements to guide physical therapist practice. The level and quality of available evidence were graded based on specific criteria to determine the strength of each action statement. Clinical algorithms were developed to guide the physical therapist in appropriate clinical decision making. Physical therapists are encouraged to work collaboratively with other members of the health care team in implementing these action statements to improve the activity, participation, and quality of life in individuals with heart failure and reduce the incidence of heart failure-related re-admissions.
... The role of pulmonary rehabilitation is well established in COPD. 36,37 Similarly, patients with PAH on medical therapy showed improvements in exercise capacity after pulmonary rehabilitation was instituted. 38 Although no studies have specifically addressed the COPD population with PH, we believe that supervised pulmonary rehabilitation is beneficial in this population. ...
... Some review works and meta-analyses on the effects of exercise interventions on COPD patients report that the combination of aerobic and strength training is generally well tolerated and provides additional muscle mass and dynamic strength gains (De Brandt et al., 2016;Man, Kemp, Moxham, & Polkey, 2009). Regarding the endurance part of the training session, aerobic interval training seems to provide better exercise tolerance, as well as higher pulmonary function and aerobic capacity improvements in comparison with continuous training (Beauchamp et al., 2010). ...
Efectos a corto y largo plazo del entrenamiento de alta intensidad en pacientes EPOC octogenarios
... PR, including exercise training as a main component, can partially reverse the morphological and structural abnormalities of peripheral muscle fibres, increase exercise performance and improve quality of life [4,5] . Several studies have reported significant improvements in the function, morphology [2,6] and metabolism of skeletal muscle following PR interventions lasting 6 or more weeks [7] . In Germany, PR is usually conducted as an inpatient program with a common duration of 3 weeks [8,9] . ...
Background
The benefits of pulmonary rehabilitation (PR) on fatigue-resistant skeletal muscle fibre type I have been found to be smaller in COPD patients with alpha-1 antitrypsin deficiency (AATD) than in those without AATD. Alpha-1 antitrypsin (AAT) augmentation therapy was suggested as a potential factor of influence. Whether this finding mirrors different improvements in 6-min walk distance (6MWD) between both groups remains unknown.
Methods
140 patients with AATD-related COPD (phenotype PiZZ, FEV1: 31 ± 8%pred.) and 280 COPD patients without AATD (FEV1: 31 ± 8%pred.) were matched for baseline 6MWD and included in a retrospective analysis. AATD patients were divided into those “on” (AATDAUG+) or “off” (AATDAUG-) augmentation therapy. 6MWD was assessed pre and post an inpatient 4-week PR program. Plasma level of creatinine was analysed at baseline.
Results
In AATD and COPD patients with comparable initial 6MWD (331 ± 106 m and 326 ± 101 m, p = n.s.), improvements in 6MWD following PR were similar (+49 ± 49 m and +53 ± 52 m, intra-group change: p < 0.001). Notably, 68% of AATD and 65% of COPD responded well with a clinically relevant 6MWD improvement of ≥30 m. The improvement in 6MWD was independent of gender, age, pack years, SF36 mental score and body mass index. The augmentation therapy with AAT did not influence 6MWD outcome (AATDAUG+: +51 ± 55 m, AATDAUG-: +47 ± 40 m, p = n.s.). Only in AATD group, higher baseline creatinine levels and lower 6MWD were positive predictors for the PR-related increase in 6MWD.
Conclusions
Independently of the genetic variant of AAT, COPD patients achieved the same training-related benefit in 6MWD. Augmentation therapy showed no effect on 6MWD adaptation during PR.
... PR, including exercise training as a main component, can partially reverse the morphological and structural abnormalities of peripheral muscle fibres, increase exercise performance and improve quality of life [4,5] . Several studies have reported significant improvements in the function, morphology [2,6] and metabolism of skeletal muscle following PR interventions lasting 6 or more weeks [7] . In Germany, PR is usually conducted as an inpatient program with a common duration of 3 weeks [8,9] . ...
Background:
Pulmonary rehabilitation (PR) improves oxidative capacity of peripheral muscles in patients with chronic obstructive pulmonary disease (COPD). The exercise-induced oxidative skeletal muscle adaptation in COPD patients with inherited alpha-1 antitrypsin deficiency (A1ATD) has not been studied.
Objectives:
To compare PR effects on skeletal muscle adaptation in COPD patients with and without A1ATD.
Methods:
Nine COPD patients with A1ATD (genotype PiZZ, 6 receiving A1AT augmentation therapy), and 10 'usual' COPD patients (genotype PiMM) performed an incremental cycling test and underwent musculus vastus lateralis biopsies before and after a 3-week PR program including exercise training.
Results:
PiZZ and PiMM patients improved peak work rate following PR (+9 ± 11 W, p < 0.05, and +18 ± 9 W, p < 0.001, between-group difference p < 0.05). PiMM patients increased fibre type I (+8.1%), reduced fibre type IIA (-2.1%) and hybrid fibre type IIA/IIX proportion (-3.9%). Following PR, PiMM patients also raised mitochondrial signalling proteins PGC-1α (4.5-fold), and TFAM (6.4-fold). PiZZ patients had no change in fibre type I but showed a shift of type IIA/IIX (-8.8%) towards fibre type IIA distribution (+8.9%). The capillary to fibre ratio increased by 28% (p < 0.05) in PiZZ, whereas no change was observed in PiMM patients. Linear regression analysis revealed that diffusion capacity and A1AT therapy are predictor variables for myofibre type I response to PR (r2 = 0.684, p < 0.01).
Conclusions:
Following a 3-week PR with comparable training modalities, PiMM but not PiZZ patients increased the oxidative myofibre type I proportion. This skeletal muscle adaptation pattern suggests better improvement of exercise capacity in PiMM than in PiZZ patients with COPD.
... Most importantly, unlike the lungs, skeletal muscle dysfunction is potentially remedial with relatively simple interventions such as exercise-training. 12 This provides an opportunity to significantly improve the symptoms and functional performance of individuals with chronic respiratory disease who often have limited pharmacological options for their lung disease. This is reflected by the increasing prominence of pulmonary rehabilitation in respiratory disease guidelines. ...
... The core components in all exercise prescription programs for COPD are endurance and strength training, although there is a lack of consensus about the intensity and duration that should be applied to the patients, especially to the oldest ones (aged ≥80 years). Some review works and meta-analyses on the effects of exercise interventions on COPD patients report that the combination of aerobic and strength training is generally well tolerated and provides additional muscle mass and dynamic strength gains (De Brandt et al., 2016; Man, Kemp, Moxham, & Polkey, 2009). Regarding the endurance part of the training session, aerobic interval training seems to provide better exercise tolerance, as well as higher pulmonary function and aerobic " Short and Long Term Effects of Concurrent Strength and HIIT Training in Octogenarian COPDs " by Guadalupe-Grau A et al. ...
To investigate the short and long time effects of concurrent strength and high intensity interval training (HIIT) on octogenarian COPD patients, nine males (age=84.2 ± 2.8 yrs, BMI=29.3 ± 2.3), with low to severe COPD level (2.1 ± 1.5 BODE index), underwent a supervised 9-week strength and HIIT exercise program. Training had a significant (P<0.05) impact on senior fitness test scores (23-45%), 30m walking speed (from 1.29 ± 0.29 to 1.62 ± 0.33 m/s), leg and chest press 1RM (38 and 45% respectively), maximal isometric strength (30-35%), and 6-minute walking test (from 286.1 ± 107.2 to 396.2 ± 106.5 m) and tended to increase predicted forced vital capacity by 14% (P=0.07). One year after the intervention all training-induced gains returned to their pre-intervention values except for the chest press 1RM (P<0.05). Short-term concurrent strength and HIIT training increases physical fitness in the oldest old COPD patients, and has potential long-term benefits.
... Neuromuscular electrical stimulation studies have largely been conducted in patients with COPD. [32] Further studies in this area are needed to determine the effects on cancer patients with dyspnea. ...
Dyspnea in patients with cancer is a common symptom and is generally associated with anxiety. It limits patients' activities of daily living and adversely affects not only patients, but also caregiv-ers. It remains a difficult symptom to manage, despite recent advances in cancer treatment and the increasing evidence available. Different pharmacological approaches such as opioids, and nonphar-macological interventions including oxygen, fun, exercise, pulmonary rehabilitation, acupuncture, acupressure and cognitive-behavioral therapies are used to manage dyspnea. Symptom management and supportive therapies given by oncology nurses become important in patients with cancer who experience dyspnea. There are limited number of publications about the management of dyspnea in Turkish oncology nursing literature. This literature review aims to inform nurses about cancer patients with dyspnea.
... La enfermedad pulmonar obstructiva crónica (EPOC) se define como una enfermedad caracterizada por la obstrucción del flujo aéreo debido a lesiones bronquiales crónicas o a enfisema, la obstrucción al flujo aéreo es generalmente progresiva, puede acompañarse de hiperreactividad de las vías aéreas y ser parcialmente reversible (1-2). Produce en los sujetos con enfermedad pulmonar avanzada alteraciones funcionales que se manifiestan con disnea e intolerancia a las actividades de la vida diaria y al ejercicio (3)(4)(5)(6)(7)(8)(9)(10). a m m m a a a n n n g g g a a a ) )) ( (( E E E n n n l ll í íí n n n e e e a a a ) )) - .. 121 actualmente se utiliza en sujetos con entidades clínicas cardiacas y pulmonares como la EPOC, valorando la tolerancia al ejercicio, necesidad de oxígeno suplementario al momento de la actividad física y respuesta al tratamiento de rehabilitación de pulmonar. ...
El test de caminata de 6 minutos, es un instrumento que permite valorar la tolerancia al ejercicio, necesidad de oxígeno suplementario al momento de la actividad física y la respuesta al tratamiento de rehabilitación en sujetos con entidades clínicas cardiacas y pulmonares principalmente; demostrando ser confiable, objetivo, seguro y de bajo costo. Se realiza ordenando al paciente caminar con una velocidad sostenida por 6 minutos, en un circuito a una distancia conocida; durante la aplicación del test se le hará un continuo monitoreo de funciones vitales, saturación de oxígeno y control de síntomas, adicionalmente, se debe evaluar la magnitud de la disnea empleando la escala de Borg versión modificada, que posee un rango de 0 a 10 puntos, siendo cero la ausencia total de dificultad respiratoria y 10 como nivel máximo. En conclusión el test se utiliza para realizar la comparación de respuesta pre y pos tratamiento de rehabilitación, estado funcional y como predictor de morbilidad y mortalidad. El objetivo del estudio fue realizar una revisión sobre el test de caminata de 6 minutos en sujetos con EPOC.
... The core components in all exercise prescription programs for COPD are endurance and strength training, although there is a lack of consensus about the intensity and duration that should be applied to the patients, especially to the oldest ones (aged ≥80 years). Some review works and meta-analyses on the effects of exercise interventions on COPD patients report that the combination of aerobic and strength training is generally well tolerated and provides additional muscle mass and dynamic strength gains (De Brandt et al., 2016; Man, Kemp, Moxham, & Polkey, 2009). Regarding the endurance part of the training session, aerobic interval training seems to provide better exercise tolerance, as well as higher pulmonary function and aerobic " Short and Long Term Effects of Concurrent Strength and HIIT Training in Octogenarian COPDs " by Guadalupe-Grau A et al. ...
... Some review works and meta-analyses on the effects of exercise interventions on COPD patients report that the combination of aerobic and strength training is generally well tolerated and provides additional muscle mass and dynamic strength gains (De Brandt et al., 2016;Man, Kemp, Moxham, & Polkey, 2009). Regarding the endurance part of the training session, aerobic interval training seems to provide better exercise tolerance, as well as higher pulmonary function and aerobic "Short and Long Term Effects of Concurrent Strength and HIIT Training in Octogenarian COPDs" by Guadalupe-Grau A et al. © 2016 Human Kinetics, Inc. capacity improvements in comparison to continuous training ( Beauchamp et al., 2010). ...
... PR, including exercise training as a main component, can partially reverse the morphological and structural abnormalities of peripheral muscle fibres, increase exercise performance and improve quality of life [4,5] . Several studies have reported significant improvements in the function, morphology [2,6] and metabolism of skeletal muscle following PR interventions lasting 6 or more weeks [7] . In Germany, PR is usually conducted as an inpatient program with a common duration of 3 weeks [8,9] . ...
Background: Exercise training improves exercise capacity in patients with chronic obstructive pulmonary diseases (COPD). In a retrospective analysis, we found that COPD patients (PiMM) showed higher improvements of exercise capacity following training intervention than Alpha-1 antitrypsin deficiency patients (A1ATD, PiZZ).
Objective: We investigated if this different change in exercise capacity is reflected by different skeletal muscle adaptations.
Methods: 6 A1ATD (PiZZ, age: 57±7y, FEV1: 38±6%pred., Prolastin®: n=6) and 10 COPD patients (PiMM, age: 62±7y, FEV1: 28±4%pred.) prospectively performed a 3-week training therapy. Before and after, each patient underwent muscle biopsy (m.vastus lateralis) and peak work rate (PWR) test.
Results: Prospective data showed that exercise capacity improved in both groups, however the improvement was smaller in A1ATD patients (PWR: A1ATD:+10±11Watt, p<0.05 vs. COPD: +19±9 Watt, p<0.001). Oxidative muscle fiber type I only increased in COPD patients (+33% [p<0.05] vs. A1ATD: -28%). A1ATD patients increased fiber type IIA by +21% whereas COPD patients decreased by -3.9%. Hybrid fibers (type I/IIA and IIA/X) decreased in both groups. Key proteins of respiratory chain and mitochondrial signaling parameters showed smaller positive adaptations in A1ATD than in COPD patients.
Discussion: Training therapy of only 3 weeks is effective in A1ATD and COPD patients. However, the effects were smaller in A1ATD patients that was mirrored by less positive adaptations in skeletal muscle regarding oxidative function and mitochondrial signaling. Further studies have to be performed to detect the mechanisms explaining these differences.
... В нашем случае у испытуемых группы "трав ма" отмечено значимое укорочение длины тела в положении сидя, частично компенсируемое у па распортсменов, вероятно, за счет активного раз вития "мышечного корсета" под воздействием регулярных занятий спортом. Косвенным при знаком улучшения функционального состояния мышц торса можно считать возрастание у парас портсменов величины дыхательного объема, ко торое связывают с повышением тренированности ФИЗИОЛОГИЯ ЧЕЛОВЕКА том 38 № 4 2012 дыхательной мускулатуры [19]. Известно, что по вреждения позвоночного столба выше Т 3 наруша ют функционирование мускулатуры, обеспечива ющей как вдох, так и выдох, и существенно сни жают объемные показатели системы внешнего дыхания [8]. ...
A comprehensive study of the functional state of basketball athletes in wheelchairs with spinal cord injuries in the T6-T10 and paraplegia (n = 9, mean age 26.6 +/- 1.7 years) was held. As a control, we used disability groups with a similar injury, leading an active life (n = 13, mean age 44.5 +/- 2.6 years), athletes ( = 14, mean age 24.6 +/- 1.3 years) and healthy physically active men (n = 15, the average age of 24.9 +/- 0.6 years). In the athletes in wheelchairs it was revealed an increase in the length of the body in a sitting position, the increase in tidal volume and increasing in the effectiveness of the functional respiratory tests. These changes in the state of the musculoskeletal system and autonomic systems to ensure physical activity classified as adaptive and due to sports training. In the state of the cardiovascular system and its autonomic regulation parasportsmen showed a reduction in trauma-induced increase in diastolic blood pressure and increase in the magnitude of arterial baroreflex sensitivity, decreased due to spinal injury. These data indicate availability of compensatory processes aimed at optimizing the cardiovascular system through the mechanisms of baroreflex regulation.
... In general, the disuse of muscle can lead to many of the features and alterations of skeletal muscle in COPD patients: muscle weakness, muscle atrophy, loss of type I fibres, decreased crosssectional area of muscle fibres, reduced oxidative enzyme activity, reduced capillary-to-fibre ratio, early lactate release, reduced rate of phosphocreatine synthesis after exercise and altered redox status (Booth & Gollnick, 1983;Coyle, Martin, Bloomfield, Lowry, & Holloszy, 1985;Larsson & Ansved, 1985;Polkey & Moxham, 2006). In healthy adults these changes are fully reversible in response to training and increased exercise; however, full recovery is unusual in COPD patients (Troosters, Gosselink, & Decramer, 2000;Polkey & Moxham, 2006Man, Kemp, Moxham & Polkey, 2009). Fig. 5, inflammation plays a key role in the activation of protein breakdown in skeletal muscle. ...
Chronic obstructive pulmonary disease (COPD) is an incurable global health burden and is characterised by progressive airflow limitation and loss of lung function. In addition to the pulmonary impact of the disease, COPD patients often develop comorbid diseases such as cardiovascular disease, skeletal muscle wasting, lung cancer and osteoporosis. One key feature of COPD, yet often underappreciated, is the contribution of oxidative stress in the onset and development of the disease. Patients experience an increased burden of oxidative stress due to the combined effects of excess reactive oxygen (ROS) and nitrogen species (RNS) generation, antioxidant depletion and reduced antioxidant enzyme activity. Currently, there is a lack of effective treatments for COPD, and an even greater lack of research regarding interventions that treat both COPD and its comorbidities. Due to the involvement of oxidative stress in the pathogenesis of COPD and many of its comorbidities, a unique therapeutic opportunity arises where the treatment of a multitude of diseases may be possible with only one therapeutic target. In this review, oxidative stress and the roles of ROS/RNS in the context of COPD and comorbid cardiovascular disease, skeletal muscle wasting, lung cancer, and osteoporosis is discussed and the potential for therapeutic benefit of anti-oxidative treatment in these conditions is outlined. Because of the unique interplay between oxidative stress and these diseases, oxidative stress represents a novel target for the treatment of COPD and its comorbidities.
Copyright © 2015. Published by Elsevier Inc.
... Eine reduzierte körperliche Belastbarkeit ist bei chronischen Atemwegs-und Lungenerkrankungen häufig. Neben Luftströmungsbegrenzungen und Einschränkungen des Lungenvolumens und Gasaustausches wurde eine Reduktion der Muskelmasse als ein ursächlicher Faktor erkannt [16,26,29]. Eine Steigerung der körperlichen Leistungsfähigkeit kann den Teufelskreis aus Inaktivität, Dekonditionierung, Verlust von Eigenständigkeit, Depressivität und schlechter Lebensqualität durchbrechen. ...
... smaller, but significant improvements in mid-thigh CSA and fat-free (FFM) mass. Certainly, it has been observed in cohort studies that up to a quarter to a third of COPD patients may not improve their exercise capacity following pulmonary rehabilitation [21] and many clinical improvements and gains from pulmonary rehabilitation decline towards baseline within 12 months. Furthermore, exercise training even in the laboratory setting does not appear to fully reverse all of the abnormalities observed in the quadriceps muscle and some investigators have used these observations to argue that inactivity may explain only part of the abnormalities observed in the peripheral muscles [22]. ...
Skeletal muscle dysfunction is one of the important systemic manifestations of chronic obstructive pulmonary disease (COPD) and is associated with mortality in those patients thus quantifying its bulk and strength is of great clinical interest and of particular value.Objective
Evaluation of quadriceps muscle bulk & strength in patients with moderate to severe stable COPD compared with normal healthy subjects and the effect of progressive resistant exercise program for 12 weeks on quadriceps muscle strength and exercise capacity.Subjects and methodsForty patients with moderate to severe stable COPD they were 26 males and 14 females. Ten healthy subjects with the same age and sex were also included as controls. All patients and controls were evaluated at baseline for quadriceps maximal voluntary contraction (QMVC), exercise capacity, the mid – thigh cross sectional area (MTCSA) and spirometric pulmonary functions then patients were classified into 2 groups only group one performed the progressive resistant exercise program for 12 weeks then reassessment of both group were done.ResultsPatients and controls were matched as regard age, weight, height and body mass index. There was significant difference between patients and control in QMVC, MTCSA, and FFM after training for 12 weeks only group one had significant difference in QMVC, MTCSA and FFM/Kg in comparison to the baseline, while there was no significant difference as regard the pulmonary functions. Also there was significant difference between group 1 and 2 after 12 weeks in QQMVC, MTCSA and FFM/kg.Conclusion
We have collected evidence indicating that both bulk and strength of quadriceps muscles in particular were reduced in patients with COPD compared with normal controls and these changes can be improved with progressive training without change in pulmonary functions.
... В нашем случае у испытуемых группы "трав ма" отмечено значимое укорочение длины тела в положении сидя, частично компенсируемое у па распортсменов, вероятно, за счет активного раз вития "мышечного корсета" под воздействием регулярных занятий спортом. Косвенным при знаком улучшения функционального состояния мышц торса можно считать возрастание у парас портсменов величины дыхательного объема, ко торое связывают с повышением тренированности ФИЗИОЛОГИЯ ЧЕЛОВЕКА том 38 № 4 2012 дыхательной мускулатуры [19]. Известно, что по вреждения позвоночного столба выше Т 3 наруша ют функционирование мускулатуры, обеспечива ющей как вдох, так и выдох, и существенно сни жают объемные показатели системы внешнего дыхания [8]. ...
The functional state in wheelchair basketball players with damage to the vertebral column in the area of T6–T10 and paraplegia was studied. The subjects were 26.6 ± 1.7 years old on average (n = 9). Control subjects were disabled persons who led an active life, with a mean age of 44.5 ± 2.6 years (n = 13), athletes with a mean age of 24.6 ± 1.3 years (n = 14), and healthy physically active men with a mean age of 24.9 ± 0.6 years (n = 15). In wheelchair athletes, the body length in the sitting posture, the respiratory volume, and the performance of respiratory tests were increased. These changes in the musculoskeletal apparatus and the systems providing autonomic regulation of motor activity may be regarded as adaptive modifications due to physical training. In the cardiovascular system of para�athletes and its autonomic regulation, attenuation of an increase in the diastolic arterial pressure value induced by injury and an elevation of sensitivity of arterial baroreflex, which had been decreased due to damage to the vertebral column, were observed. These data indicate compensatory processes adjusting the functioning of the cardiovascular system via the mechanisms of baroreflex regulation.
... 27 Moreover, this would be in keeping with the more recent concepts that muscle mass loss in COPD is due to deconditioning, exacerbations, and hypoxia. 28,29 It may be that the role of inflammation in muscle mass loss is more closely linked to infective exacerbations, an aspect that is beyond the scope of this study. Previous COPD studies have found that skeletal muscle depletion prevalence ranges between 10% and 40%, 3,30,31 which is consistent with our findings. ...
Background:
Nutritional depletion is an important manifestation of chronic obstructive pulmonary disease (COPD), which has been related to systemic inflammation. It remains unclear to what degree airway inflammation contributes to the presence or progression of nutritional depletion.
Objectives:
To determine whether airway inflammation and lung bacterial colonization are related to nutritional status or predict progressive weight loss and muscle atrophy in patients with COPD.
Methods:
Body composition using dual energy X-ray absorptiometry, indices of airway inflammation, and bacterial colonization were measured in 234 COPD patients. Systemic inflammation was assessed from serum C reactive protein (CRP) and circulating total and differential leukocyte counts. Nutritional depletion was defined as a body mass index (BMI) less than 21 kg/m(2) and/or fat-free mass index (FFMI) less than 15 or 17 kg/m(2) in women and men, respectively. FFMI was calculated as the fat-free mass (FFM) corrected for body surface area. Measurements were repeated in 94 patients after a median 16-month follow-up. Regression analysis was used to assess the relationships of weight change and FFM change with indices of bacterial colonization and airway and systemic inflammation.
Results:
Nutritional depletion occurred in 37% of patients. Lung function was worsened in patients with nutritional depletion compared to those without (forced expiratory volume in 1 second 1.17 L versus 1.41 L, mean difference 0.24, 95% confidence interval 0.10 to 0.38, P<0.01). There were no differences in airway inflammation and bacterial colonization in patients with and without nutritional depletion. At baseline, BMI correlated positively with serum CRP (rs=0.14, P=0.04). Change in weight and change in FFM over time could not be predicted from baseline patient characteristics.
Conclusion:
Nutritional depletion and progressive muscle atrophy are not related to airway inflammation or bacterial colonization. Overspill of pulmonary inflammation is not a key driver of muscle atrophy in COPD.
... Eine reduzierte körperliche Belastbarkeit ist bei chronischen Atemwegs-und Lungenerkrankungen häufig. Neben Luftströmungsbegrenzungen und Einschränkungen des Lungenvolumens und Gasaustausches wurde eine Reduktion der Muskelmasse als ein ursächlicher Faktor erkannt [16,26,29]. Eine Steigerung der körperlichen Leistungsfähigkeit kann den Teufelskreis aus Inaktivität, Dekonditionierung, Verlust von Eigenständigkeit, Depressivität und schlechter Lebensqualität durchbrechen. ...
Background
Pulmonary rehabilitation is a well-recognized treatment option in chronic obstructive lung disease improving exercise performance, respiratory symptoms and quality of life. In occupational respiratory diseases very little information is available.
Objectives
The goal of this study was to evaluate the usefulness and sustainability of pulmonary rehabilitation in patients with occupational respiratory diseases, partly involving complex alterations of lung function.
Methods
We studied 263 patients (asthma, silicosis, asbestosis, chronic obstructive pulmonary disease) using a 4-week inpatient rehabilitation program and follow-up examinations 3 and 12 months later. The outcomes evaluated were lung function, 6-min walking distance (6MWD), maximum exercise capacity (Wmax), skeletal muscle strength, respiratory symptoms, exacerbations and associated medical consultations, quality of life [Short Form, 36 items (SF-36), Saint George’s Respiratory Questionnaire (SGRQ)], anxiety/depression [Hospital Anxiety and Depression Scale (HADS)] and breathlessness [Medical Research Council (MRC) dyspnea scale, Baseline/Transition Dyspnea Index (BDI/TDI)].
Results
Compared to baseline, there were significant (p < 0.05) improvements in 6MWD, Wmax and muscle strength immediately after rehabilitation, and these were maintained over 12 months (p < 0.05). Effects were less pronounced in asbestosis. Overall, significant reductions in the rate of exacerbations by 35 %, antibiotic therapy by 27 % and use of health care services by 17 % were observed compared to the previous year. No changes were seen in the questionnaire outcomes.
Conclusion
Pulmonary rehabilitation is effective even in the complex settings of occupational respiratory diseases, providing sustained improvement of functional capacity and reducing health care utilization.
... In our study, we observed a significant shortening of the body height in the sitting position in subjects of the injury group, which, in para athletes, was compen sated due to the development of a muscle corset as a consequence of regular training. An indirect sign of improvement of the functional state of trunk muscles is an increase in respiratory volume in the para ath letes, which is probably related to their better trained respiratory muscles [19]. Damage to the vertebral col umn above Т 3 is known to impair the functioning of the muscles that are responsible for both inspiration and expiration [8]. ...
The functional state in wheelchair basketball players with damage to the vertebral column in the area of T
6-T
10 and paraplegia was studied. The subjects were 26.6 ± 1.7 years old on average (n = 9). Control subjects were disabled persons who led an active life, with a mean age of 44.5 ± 2.6 years (n = 13), athletes with a mean age of 24.6 ± 1.3 years (n = 14), and healthy physically active men with a mean age of 24.9 ± 0.6 years (n = 15). In wheelchair athletes, the body length in the sitting posture, the respiratory volume, and the performance of respiratory tests were increased. These changes in the musculoskeletal apparatus and the systems providing autonomic regulation of motor activity may be regarded as adaptive modifications due to physical training. In the cardiovascular system of para-athletes and its autonomic regulation, attenuation of an increase in the diastolic arterial pressure value induced by injury and an elevation of sensitivity of arterial baroreflex, which had been decreased due to damage to the vertebral column, were observed. These data indicate compensatory processes adjusting the functioning of the cardiovascular system via the mechanisms of baroreflex regulation.
... 8,9 Skeletal muscle dysfunction in patients with chronic obstructive pulmonary disease (COPD), especially quadriceps femoris weakness, affects the exercise capacity abnormally and contributes to poor exercise capacity and health status, health care utilization, and mortality. 10 Heart failure and COPD are 2 prevalent diseases; they have many common characteristics like exercise intolerance, muscle weakness, dyspnea, and fatigue. So far, the relationship between lower extremity muscle weakness and exercise capacity has been studied in heart failure. ...
Aims: The aims of this study were to investigate the relationship between functional capacity and pulmonary function, respiratory and peripheral muscle strength, and find out the best predictor of functional capacity in patients with heart failure. Design: A prospective, cross sectional study.
Subjects and Methods: Thirty-four clinically stable patients with heart failure (68.59 ± 9.85 years, left ventricular ejection fraction = 34.24% ± 7.59%, New York Heart Association class II/III) were included. Patients' characteristics were recorded. Functional capacity was evaluated using 6-minute walk test (6MWT). Pulmonary function was measured using spirometry, respiratory muscle strength (maximum inspiratory pressure and maximum expiratory pressure) was measured using a mouth pressure device, and quadriceps femoris and biceps brachii muscle strengths were assessed using a hand-held dynamometer.
Results: There were statistically significant positive correlations between 6MWT distance and pulmonary function, maximum inspiratory pressure, maximum expiratory pressure, quadriceps femoris and biceps brachii muscle strengths (P < .05). In the multiple regression analysis conducted in the 34 heart failure patients, 79% of the variance in the 6MWT distance was explained by qaudriceps femoris (R2 = 0.70, P < .001) and the biceps brachii (R2 = .09, P = .007) muscle strengths. When the 6MWT distance was expressed as the percentage of predicted values, 58% of the variance in the 6MWT distance was explained by qaudriceps femoris (R2 = 0.40, P = .001) and the percent biceps brachii muscle strength (R2 = 0.18, P = .007).
Conclusions: Upper and lower extremity muscle strength is a factor significantly contributing to impaired functional capacity in patients with heart failure. These findings suggest that routine screening of upper and lower extremity muscle strengths is advisable in patients with heart failure.
... Typically, chronic endurance training enhances the fatigue resistance of skeletal muscle by promoting a muscle-fiber type shift from fast-twitch fatigable type II fibers to slow-twitch fatigue-resistant type I fibers, increasing mitochondrial content and activity and improving skeletal muscle glucose transportation. However, resistance training reduces sarcopenia and promotes hypertrophy of muscle fibers, especially of type IIx.143 ...
The skeletal muscles play an essential role in life, providing the mechanical basis for respiration and movement. Skeletal muscle dysfunction is prevalent in all stages of chronic obstructive pulmonary disease (COPD), and significantly influences symptoms, functional capacity, health related quality of life, health resource usage and even mortality. Furthermore, in contrast to the lungs, the skeletal muscles are potentially remedial with existing therapy, namely exercise-training. This review summarizes clinical and laboratory observations of the respiratory and peripheral skeletal muscles (in particular the diaphragm and quadriceps), and current understanding of the underlying etiological processes. As further progress is made in the elucidation of the molecular mechanisms of skeletal muscle dysfunction, new pharmacological therapies are likely to emerge to treat this important extra-pulmonary manifestation of COPD.
... 12 PR programmes during a SECOPD are difficult to implement due to the clinical condition of these patients, and strategies avoiding respiratory system stress are needed. 13 Neuromuscular electrical stimulation (NMES) is a muscle training technique that has been used in diverse conditions, such as stroke, orthopaedic surgery, chronic heart failure and also in COPD 14e16 incurring minimal stress to the respiratory system. 14,17 Moreover, it is relatively inexpensive and patients can be trained to self-administer NMES constituting an ideal strategy to prevent skeletal muscle deterioration occurring during SECOPD. ...
COPD is a condition with systemic effects of which peripheral muscle dysfunction is a prominent contributor to exercise limitation, health related quality of life (HRQoL) impairment, and is an independent predictor of morbidity and mortality. Pulmonary rehabilitation (PR) is a successful strategy to improve exercise tolerance and HRQoL through the improvement of muscle function in patients with stable COPD or early after severe exacerbations of COPD (SECOPD). However, muscle function further deteriorates during SECOPD before early PR programmes commence. We aimed to investigate the feasibility and efficacy of quadriceps neuromuscular electrical stimulation (NMES) applied during a SECOPD to prevent muscle function deterioration.
We have conducted a pilot study in eleven COPD patients (FEV(1) 41.3 ± 5.6 % pred) admitted to hospital with a SECOPD. We randomly allocated one leg to receive NMES (once a day for 14 days) with the other leg as a control (non-stimulated leg). We measured the change in quadriceps maximal voluntary contraction (ΔQMVC) as the main outcome.
Mean quadriceps muscle strength decreased in control legs (ΔQMVC -2.9 ± 5.3 N, p = ns) but increased in the stimulated legs (ΔQMVC 19.2 ± 6.1 N, p < 0.01). The difference in ΔQMVC between groups was statistically significant (p < 0.05). The effect of NMES was directly related to the stimulation intensity (∑mA) applied throughout the 14 sessions (r = 0.76, p < 0.01). All patients tolerated NMES without any side effects.
NMES is a feasible and effective treatment to prevent quadriceps muscle strength derangement during severe exacerbations of COPD and may be used to compliment early post-exacerbation pulmonary rehabilitation.
Background
To compare the effectiveness of ES and TS plus exercise breathing after discharge on mechanically ventilated patients with chronic obstructive pulmonary disease (COPD) to those receiving standard care in terms of 30-day mortality, hospital readmission, and health-related quality of life (HRQOL).
Patients and methods
The current study was a randomized controlled trial. It included 108 newly admitted patients with COPD to RICU, Chest Department, Assiut University Hospital, Egypt, between June 2018 and May 2020. They were divided into two groups: group I received the usual care plus ES and TS plus breathing exercise, and group II received the usual care alone. Thirty-day mortality, hospital readmission, and HRQOL assessed by MFR-28 were recorded and evaluated. Student t test, Mann–Whitney U test, χ ² test, and Fisher exact test were performed to analyze the data.
Results
A total of 108 patients with COPD were included. Early rehabilitation program (ES and TS) plus exercise breathing for patients with COPD in the ICU showed decreased 30-day mortality, decreased hospital readmission, and improved HRQOL as compared with patients with COPD who received usual care.
Conclusion
Patients with COPD who were treated with an early rehabilitation program (ES and TS) combined with exercise breathing had a better prognosis and a higher QOL.
Clinical trial.gov
The study was registered under NCT03253380.
The loss of muscle proteins due to acute and chronic disease, or inactivity and aging, is commonly referred to as muscle atrophy or wasting. Prevention and treatment of muscle wasting is increasingly recognized as a prerequisite in an integrated disease management approach of chronic disorders such as chronic obstructive pulmonary disease (COPD) and cancer.
This PhD project (Department of Respiratory Medicine) was aimed at elucidating the molecular mechanisms that underlie skeletal muscle atrophy and focused specifically on the role of GSK-3β, a key signaling protein in the modulation of skeletal muscle plasticity. We concluded that GSK-3β is a central, negative regulator of muscle mass maintenance.
COPD is associated with symptoms and non-pulmonary manifestations which are potentially amenable to exercise training, primarily through pulmonary rehabilitation. Pulmonary rehabilitation, an exercise and education program, is an integral component in the non-pharmacological strategy for COPD. This article outlines the evolution of pulmonary rehabilitation, the evidence-base for this intervention in people with COPD, the typical program format and content, the maintenance of pulmonary rehabilitation, and the implementation into clinical practice.
Resumen
Antecedentes/objetivo
La duración de los efectos de la rehabilitación pulmonar (RP) en pacientes con enfermedad pulmonar obstructiva crónica (EPOC) es limitada. El objetivo del estudio fue describir los efectos a corto y largo plazo de varias modalidades de programas clínicos de RP en pacientes con EPOC e identificar los posibles factores influyentes.
Pacientes/métodos
Estudio observacional longitudinal retrospectivo. Sujetos con EPOC (n = 35) que recibieron uno de los siguientes programas clínicos de RP (8 semanas): PRP1 (entrenamiento aeróbico), PRP2 (entrenamiento aeróbico-fuerza) y PRP3 (entrenamiento aeróbico-fuerza-músculos respiratorios). Variables: capacidad de ejercicio (distancia en la Prueba de Marcha de Seis Minutos, 6MWD), disnea (escala modificada del Medical Research Council, mMRC) y presiones respiratorias (solo PRP3), evaluadas pretratamiento, postratamiento y tras 12 meses.
Resultados
Postratamiento mejoró la 6MWD (59,1 ± 27,3 m; p < 0,01) y se redujo la escala mMRC (−0,7 ± 0,4; p < 0,01). Tras 12 meses desde el postratamiento, se produjo un declive en la 6MWD (−49,8 ± 23 m; p < 0,01) y un incremento en la escala mMRC (0,7 ± 0,4; p < 0,01). Estos resultados fueron ligeramente superiores en los grupos PRP2 y PRP3, pero sin diferencias significativas (p > 0,05). Un comportamiento similar se observó en las presiones respiratorias. Se analizaron los posibles factores influyentes en el declive en la 6MWD durante el seguimiento. Solo se encontró una correlación significativa e inversa entre el incremento en la 6MWD postratamiento y su declive postseguimiento (r = −0,52; p < 0,01).
Conclusión
Los programas convencionales de RP en EPOC mejoran la capacidad de ejercicio y la disnea, pero estos beneficios se pierden tras 12 meses sin mantenimiento. El incremento en la 6MWD tras la RP puede ser un factor pronóstico del declive en la tolerancia al ejercicio.
Limb muscle dysfunction is frequent in COPD and contributes to its morbidity and mortality. Limb muscle dysfunction encompasses several manifestations including muscle atrophy and weakness, susceptibility to muscle fatigue and reduced oxidative capacity and mitochondrial function. Depending on the criteria used, up to a third of patients with COPD expresses some form of muscle dysfunction, including atrophy and weakness [1]. Although the extent of muscle atrophy and weakness is greater in more advanced disease, it is important to recognize that muscle dysfunction may also occur in early disease [1, 2]. The typical patients with COPD entering a pulmonary rehabilitation program have already lost about 30% of muscle mass and strength [3]. One important aspect of limb muscle dysfunction is that it is amenable to therapy, the most effective for this problem being exercise training [4–7]. Arguably, the most perverse consequence of muscle dysfunction is its negative effect on life expectancy. Parameters such as reduced mid-thigh cross-sectional area [8], fat-free mass [9], lower quadriceps strength [10] and vastus lateralis fibre-type shift [11] are predictors of mortality in subjects with COPD. Beyond its negative impact on survival, limb muscle dysfunction also contributes to exercise intolerance in COPD and poor quality of life in this disease. For example, quadriceps strength is a strong determinant of exercise capacity [12]. Premature leg fatigue reduces the ability of bronchodilators to enhance exercise tolerance [13, 14]. The links that exist between limb muscle function and relevant clinical outcomes in COPD stress out the importance for clinicians to carefully monitor body composition and muscle function when evaluating a patient with COPD, particularly before pulmonary rehabilitation where one goal of the intervention is to improve limb muscle function.
Background:
This review is an update of a previously published review in the Cochrane Database of Systematic Reviews Issue 1, 2013 on Neuromuscular electrical stimulation for muscle weakness in adults with advanced disease.Patients with advanced progressive disease often experience muscle weakness, which can impact adversely on their ability to be independent and their quality of life. In those patients who are unable or unwilling to undertake whole-body exercise, neuromuscular electrical stimulation (NMES) may be an alternative treatment to enhance lower limb muscle strength. Programmes of NMES appear to be acceptable to patients and have led to improvements in muscle function, exercise capacity, and quality of life. However, estimates regarding the effectiveness of NMES based on individual studies lack power and precision.
Objectives:
Primary objective: to evaluate the effectiveness of NMES on quadriceps muscle strength in adults with advanced disease. Secondary objectives: to examine the safety and acceptability of NMES, and its effect on peripheral muscle function (strength or endurance), muscle mass, exercise capacity, breathlessness, and health-related quality of life.
Search methods:
We identified studies from searches of the Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (CDSR), and Database of Abstracts of Reviews of Effects (DARE) (the Cochrane Library), MEDLINE (OVID), Embase (OVID), CINAHL (EBSCO), and PsycINFO (OVID) databases to January 2016; citation searches, conference proceedings, and previous systematic reviews.
Selection criteria:
We included randomised controlled trials in adults with advanced chronic respiratory disease, chronic heart failure, cancer, or HIV/AIDS comparing a programme of NMES as a sole or adjunct intervention to no treatment, placebo NMES, or an active control. We imposed no language restriction.
Data collection and analysis:
Two review authors independently extracted data on study design, participants, interventions, and outcomes. We assessed risk of bias using the Cochrane 'Risk of bias' tool. We calculated mean differences (MD) or standardised mean differences (SMD) between intervention and control groups for outcomes with sufficient data; for other outcomes we described findings from individual studies. We assessed the evidence using GRADE and created a 'Summary of findings' table.
Main results:
Eighteen studies (20 reports) involving a total of 933 participants with COPD, chronic respiratory disease, chronic heart failure, and/or thoracic cancer met the inclusion criteria for this update, an additional seven studies since the previous version of this review. All but one study that compared NMES to resistance training compared a programme of NMES to no treatment or placebo NMES. Most studies were conducted in a single centre and had a risk of bias arising from a lack of participant or assessor blinding and small study size. The quality of the evidence using GRADE comparing NMES to control was low for quadriceps muscle strength, moderate for occurrence of adverse events, and very low to low for all other secondary outcomes. We downgraded the quality of evidence ratings predominantly due to inconsistency among study findings and imprecision regarding estimates of effect. The included studies reported no serious adverse events and a low incidence of muscle soreness following NMES.NMES led to a statistically significant improvement in quadriceps muscle strength as compared to the control (12 studies; 781 participants; SMD 0.53, 95% confidence interval (CI) 0.19 to 0.87), equating to a difference of approximately 1.1 kg. An increase in muscle mass was also observed following NMES, though the observable effect appeared dependent on the assessment modality used (eight studies, 314 participants). Across tests of exercise performance, mean differences compared to control were statistically significant for the 6-minute walk test (seven studies; 317 participants; 35 m, 95% CI 14 to 56), but not for the incremental shuttle walk test (three studies; 434 participants; 9 m, 95% CI -35 to 52), endurance shuttle walk test (four studies; 452 participants; 64 m, 95% CI -18 to 146), or for cardiopulmonary exercise testing with cycle ergometry (six studies; 141 participants; 45 mL/minute, 95% CI -7 to 97). Limited data were available for other secondary outcomes, and we could not determine the most beneficial type of NMES programme.
Authors' conclusions:
The overall conclusions have not changed from the last publication of this review, although we have included more data, new analyses, and an assessment of the quality of the evidence using the GRADE approach. NMES may be an effective treatment for muscle weakness in adults with advanced progressive disease, and could be considered as an exercise treatment for use within rehabilitation programmes. Further research is very likely to have an important impact on our confidence in the estimate of effect and may change the estimate. We recommend further research to understand the role of NMES as a component of, and in relation to, existing rehabilitation approaches. For example, studies may consider examining NMES as an adjuvant treatment to enhance the strengthening effect of programmes, or support patients with muscle weakness who have difficulty engaging with existing services.
The respiratory muscle dysfunction due to muscle atrophy can occur in numerous pathologies such as cancer, collagen disease, chronic obstructive pulmonary disease (COPD), and diaphragm unloading via mechanical ventilation. Several proteolytic pathways including lysosomal proteases such as calpain and ubiquitin proteasome systems are involved in the degradation of muscle proteins, and abundant evidence implicates oxidative stress as a potential regulator of proteolytic pathways leading to muscle atrophy. Several lines of evidence demonstrate that an increase in protein oxidation is involved in the increased diaphragmatic proteolysis during mechanical ventilation. Also, skeletal muscle dysfunction is associated with poor health status in patients with COPD. Recent evidence supports a strong role for oxidative/nitrative stress in depressed skeletal muscle strength and endurance in COPD. A growing number of studies suggest that antioxidant can serve as therapeutic agents in delaying the muscle atrophy. This chapter will address the role of oxidative and nitrative stress in muscle dysfunction of respiratory diseases.
Dysfunction of respiratory and limb muscles is recognized as a major systemic manifestation of COPD. This dysfunction further increases the disease's morbidity and should be properly evaluated. The aim of this chapter is to summarize the current knowledge on the structural and functional adaptations of both muscle groups in response to COPD. An overview of the possible mechanisms that could explain the development of muscle dysfunction in COPD is also provided. Finally, a summary of the available treatments of muscle dysfunction is presented and their efficiency is discussed.
Objective: To compare the effects of high-intensity and low-intensity aerobic exercises on pulmonary ventilation function and exercise endurance of patients with mild to moderate chronic obstructive pulmonary disease(COPD). Method: Sixty patients with COPD were divided into high-intensity (with 70% peak power) aerobic exercise group (n=20), low-intensity (with 50% peak power) aerobic exercise group (n=20) and control group (n=20). All patients administered cardiopulmonary exercise test(CPET) before and after training period, aerobic exercise duration was 8 weeks, 3 times every week. High intensity group did exercise for 40min per time with 4 sections, and each section lasted 5min with 5min interval, while low-intensity group administered 20min continuously exercise every time. Result:There was no significant difference(P>0.05) in all variables in three groups before training. After training, compared with before training the differences of exercise endurance duration, peak power and peak VO2 among three groups were significantly different (P<0.05), and high-intensity group improved more than that of other groups; there was no significant difference between control group and lower-intensity group in peak ventilation (VE) (P>0.05), but significant difference between high-intensity group and other groups(P<0.05). Anaerobic threshold (AT) of high-intensity group increased more than that of control group(P<0.05). Conclusion: Comparing with lower-intensity aerobic exercise, high-intensity interval aerobic exercise can significantly improve the pulmonary ventilation function and exercise endurance in patients with mild to moderate COPD.
Chronic obstructive pulmonary disease (COPD) is now well recognized as a systemic disorder. Apart from the lungs, the musculoskeletal system is one of the most frequently affected organs. Skeletal muscle dysfunction contributes independently to symptoms, impaired health status, increased health care resource usage, and reduced survival. Pulmonary impairment is largely irreversible and therefore the skeletal muscles represent a potential site to improve functioning and symptoms in patients with COPD. The etiology of skeletal muscle dysfunction in COPD is probably multifactorial with varying contributions from physical inactivity, systemic inflammation, hormone imbalance, tissue hypoxia, nutritional abnormalities, oxidative stress, genetic susceptibility, and chronic corticosteroid use. Exercise training is effective at reversing skeletal muscle dysfunction, and pulmonary rehabilitation, a largely exercise-based intervention, has become a cornerstone in the management of COPD. This article summarizes the structural and functional characteristics of skeletal muscle dysfunction in COPD, reviews the possible contributing factors, and describes the effect of pulmonary rehabilitation on skeletal muscle structure and function.
Background: Osteoarthritis (OA) has a very high rate of comorbidity. Exercise therapy is recommended in current guidelines on the management of OA of the hip and knee. Unfortunately, current protocols and guidelines for exercise therapy in OA of the hip and knee do not offer advice concerning comorbidity-associated adaptations for exercise therapy in OA patients. Because of the high prevalence of comorbidity in OA, it is important to establish when exercise therapy for OA of the hip and knee should be adapted when patients have one or more comorbidities.
Objective: To identify restrictions and contraindications for exercise therapy for common comorbidities (cardiac diseases, hypertension, type 2 diabetes, obesity, chronic obstructive pulmonary disease (COPD), depression, chronic pain, low back pain (LBP), visual or hearing impairments, and chronic cystitis) in hip and knee OA patients.
Major findings: Cardiac diseases, hypertension, type 2 diabetes, COPD, and chronic cystitis are associated with restrictions resulting from physiological impairments. Conversely, LBP, chronic pain syndromes, and depression are associated with psychological and behavioural restrictions to exercise therapy. Visual and hearing impairments result predominantly in environmental restrictions to exercise. Obesity is associated with restrictions resulting from physiological and psychological impairments and behavioural barriers. Several absolute contraindications exist and patient safety cannot be guaranteed when these are not taken into account during exercise therapy.
Conclusion: Restrictions and contraindications for exercise in patients with OA of the hip and knee and comorbidity have been identified. This overview is helpful in decisions on the treatment of patients and will be instrumental in the development of a protocol for comorbidity related adaptations in exercise therapy for OA patients.
The systemic effects and comorbidities of chronic respiratory disease such as COPD contribute substantially to its burden. Symptoms in COPD do not solely arise from the degree of airflow obstruction as exercise limitation is compounded by the specific secondary manifestations of the disease including skeletal muscle impairment, osteoporosis, mood disturbance, anemia, and hormonal imbalance. Pulmonary rehabilitation targets the systemic manifestations of COPD, the causes of which include inactivity, systemic inflammation, hypoxia and corticosteroid treatment. Comorbidities are common, including cardiac disease, obesity, and metabolic syndrome and should not preclude pulmonary rehabilitation as they may also benefit from similar approaches.
COPD is characterized by airflow limitation that is not fully reversible. The morphological basis for airflow obstruction results from a varying combination of obstructive changes in peripheral conducting airways and destructive changes in respiratory bronchioles, alveolar ducts, and alveoli. A reduction of vascularity within the alveolar septa has been reported in emphysema. Typical physiological changes reflect these structural abnormalities. Spirometry documents airflow obstruction when the FEV1/FVC ratio is reduced below the lower limit of normality, although in early disease stages FEV1 and airway conductance are not affected. Current guidelines recommend testing for bronchoreversibility at least once and the postbronchodilator FEV1/FVC be used for COPD diagnosis; the nature of bronchodilator response remains controversial, however. One major functional consequence of altered lung mechanics is lung hyperinflation. FRC may increase as a result of static or dynamic mechanisms, or both. The link between dynamic lung hyperinflation and expiratory flow limitation during tidal breathing has been demonstrated. Hyperinflation may increase the load on inspiratory muscles, with resulting length adaptation of diaphragm. Reduction of exercise tolerance is frequently noted, with compelling evidence that breathlessness and altered lung mechanics play a major role. Lung function measurements have been traditionally used as prognostic indices and to monitor disease progression; FEV1 has been most widely used. An increase in FVC is also considered as proof of bronchodilatation. Decades of work has provided insight into the histological, functional, and biological features of COPD. This has provided a clearer understanding of important pathobiological processes and has provided additional therapeutic options. © 2014 American Physiological Society. Compr Physiol 4:1-31, 2014.
Sarcopenia is a relatively new concept in the medical literature, initially intended to describe the loss of lean body mass that occurs with aging. More recently, sarcopenia has been described in various forms of chronic disease, including patients with end-stage organ disease awaiting transplantation. The presence of sarcopenia is an important marker in transplant patients, since it has been linked to poorer pre- and posttransplant outcomes compared with patients with preserved muscle mass. The mechanisms and natural history of sarcopenia in transplant patients are incompletely understood, and there are currently no therapies proven to mitigate or reverse the process. This article reviews the current understanding of the prevalence and clinical significance of sarcopenia in transplant patients and highlights important areas of future research.
Background:
Patients with progressive diseases often experience muscle weakness, which impacts adversely on levels of independence and quality of life. In those who are unable or unwilling to undertake traditional forms of exercise, neuromuscular electrical stimulation (NMES) may provide an alternative method of enhancing leg muscle strength. Programmes appear to be well tolerated and have led to improvements in muscle function, exercise capacity and quality of life. However, estimates regarding the effectiveness of NMES from individual studies lack power and precision.
Objectives:
Primary objective:
to evaluate the effectiveness of NMES for improving muscle strength in adults with advanced disease.
Secondary objective:
to examine the acceptability and safety of NMES, and changes in muscle function (strength or endurance), muscle mass, exercise capacity, breathlessness and health-related quality of life.
Search methods:
Studies were identified from searches of The Cochrane Library, MEDLINE, EMBASE, CINAHL and PsycINFO databases to July 2012, citation searches, conference proceedings and previous systematic reviews.
Selection criteria:
We included randomised controlled trials (RCTs) in adults with advanced chronic obstructive pulmonary disease (COPD), chronic heart failure, cancer or human immunodeficiency virus/acquired immunodeficency syndrome (HIV/AIDS) comparing a programme of NMES as a sole or adjunct intervention to no treatment, placebo NMES or an active control. We imposed no language restriction.
Data collection and analysis:
Two review authors independently extracted data on study design, participants, interventions and outcomes. We assessed risk of bias using the Cochrane Collaboration's tool. We calculated mean differences (MD) or standardised mean differences (SMD) between intervention and control groups for outcomes with sufficient data; for other outcomes we described findings from individual studies.
Main results:
Eleven studies involving a total of 218 participants met the inclusion criteria across COPD, chronic heart failure and thoracic cancer. NMES significantly improved quadriceps strength by a SMD of 0.9 (95% confidence interval (CI) 0.33 to 1.46), equating to approximately 25 Newton metres (Nm) (95% CI 9 to 41). Mean differences across various walking tests, favouring NMES, were 40 m (95% CI -4 to 84) for the six-minute walk test, 69 m (95% CI 19 to 119) for the incremental shuttle walk test and 160 m (95% CI 34 to 287) for the endurance shuttle walk test. Limited evidence was available for the assessment of other secondary outcomes.
Authors' conclusions:
NMES appears an effective means of improving muscle weakness in adults with progressive diseases such as COPD, chronic heart failure and cancer. Further research is required to clarify its place in clinical practice, by determining the optimal parameters for a NMES programme, the patients most likely to benefit, and its impact on morbidity and service use.
A randomized, controlled, single-blind study was performed on 20 patients with chronic obstructive pulmonary disease and exercise-induced hypoxaemia. Ten patients each were randomly assigned to one of two groups, one training with air and the other training with oxygen. There were no signi cant differences between the groups regarding values measured prior to the study. The patients trained 3 times per week for 30 minutes each time for a duration of 8 weeks. The training consisted of interval walking on a treadmill (intensity set according to Borg ratings) with either air or oxygen administered through a nasal cannula at a rate of 5 l/min. Training signii cantly improved the 6-minute walking distance by 20% and 14% in the air and oxygen group, respectively, when the patients were tested on air. In the same test the air group signii cantly decreased Borg ratings for perceived exertion. Borg ratings for dyspnoea and perceived exertion signi cantly decreased in the oxygen group when they were tested on oxygen. It was concluded that oxygen supplementation did not further improve the training effect, compared with training with air, in patients with chronic obstructive pulmonary disease and exercise-induced hypoxaemia.
The peroxisome proliferator-activated receptor (PPAR)-gamma coactivator-1 (PGC-1) can induce mitochondria biogenesis and has been implicated in the development of oxidative type I muscle fibers. The PPAR isoforms alpha, beta/delta, and gamma control the transcription of genes involved in fatty acid and glucose metabolism. As endurance training increases skeletal muscle mitochondria and type I fiber content and fatty acid oxidative capacity, our aim was to determine whether these increases could be mediated by possible effects on PGC-1 or PPAR-alpha, -beta/delta, and -gamma. Seven healthy men performed 6 weeks of endurance training and the expression levels of PGG-1 and PPA-R-alpha, -beta/delta, and -gamma mRNA as well as the fiber type distribution of the PGC-1 and PPAR-alpha proteins were measured in biopsies from their vastus lateralis muscle. PGC-1 and PPAR-a mRNA expression increased by 2.7- and 2.2-fold (P < 0.01), respectively, after endurance training. PGC-1 expression was 2.2- and 6-fold greater in the type IIa than in the type I and IIx fibers, respectively. It increased by 2.8-fold in the type IIa fibers and by 1.5-fold in both the type I and IIx fibers after endurance training (P < 0.015). PPAR-alpha was 1.9-fold greater in type I than in the II fibers and increased by 3.0-fold and 1.5-fold in these respective fibers after endurance training (P < 0.001). The increases in PGC-1 and PPAR-alpha levels reported in this study may play an important role in the changes in muscle mitochondria content, oxidative phenotype, and sensitivity to insulin known to be induced by endurance training.
Peroxisome proliferator-activated receptor a (PPARa) plays a key role in the transcriptional control of genes encoding mitochondrial fatty acid b-oxidation (FAO) enzymes. In this study we sought to determine whether the recently identified PPAR gamma coactivator 1 (PGC-1) is capable of coactivating PPARa in the transcriptional control of genes encoding FAO enzymes. Mammalian cell cotransfection experiments demon- strated that PGC-1 enhanced PPARa-mediated transcriptional activation of reporter plasmids containing PPARa target elements. PGC-1 also enhanced the transactivation activity of a PPARa-Gal4 DNA binding domain fusion protein. Retroviral vector-mediated expression studies performed in 3T3-L1 cells demonstrated that PPARa and PGC-1 cooperatively induced the expression of PPARa target genes and increased cellular palmitate oxidation rates. Glutathione S-transferase "pulldown" studies revealed that in contrast to the previously reported ligand-independent interaction with PPARg, PGC-1 binds PPARa in a ligand-influenced manner. Protein-protein interaction studies and mammalian cell hybrid experiments demonstrated that the PGC-1-PPARa interaction involves an LXXLL domain in PGC-1 and the PPARa AF2 region, consistent with the observed ligand influence. Last, the PGC-1 transactivation domain was mapped to within the NH2-terminal 120 amino acids of the PGC-1 molecule, a region distinct from the PPARa interacting domains. These results identify PGC-1 as a coactivator of PPARa in the transcriptional control of mitochondrial FAO capacity, define separable PPARa interaction and transactivation domains within the PGC-1 molecule, and demonstrate that certain features of the PPARa-PGC-1 interaction are distinct from that of PPARg-PGC-1.
Amyloid-beta peptide is central to the pathology of Alzheimer's disease, because it is neurotoxic—directly by inducing oxidant stress, and indirectly by activating microglia. A specific cell-surface acceptor site that could focus its effects on target cells has been postulated but not identified. Here we present evidence that the 'receptor for advanced glycation end products' (RAGE) is such a receptor, and that it mediates effects of the peptide on neurons and microglia. Increased expression of RAGE in Alzheimer's disease brain indicates that it is relevant to the pathogenesis of neuronal dysfunction and death.
COPD (chronic obstructive pulmonary disease), although primarily a disease of the lungs, exhibits secondary systemic manifestations. The skeletal muscles are of particular interest because their function (or dysfunction) not only influences the symptoms that limit exercise, but may contribute directly to poor exercise performance. Furthermore, skeletal muscle weakness is of great clinical importance in COPD as it is recognized to contribute independently to poor health status, increased healthcare utilization and even mortality. The present review describes the current knowledge of the structural and functional abnormalities of skeletal muscles in COPD and the possible aetiological factors. Increasing knowledge of the molecular pathways of muscle wasting will lead to the development of new therapeutic agents and strategies to combat COPD muscle dysfunction.
Cellular migration is a fundamental process linked to diverse pathological states such as diabetes and its complications, atherosclerosis, inflammation, and cancer. The receptor for advanced glycation end products (RAGE) is a multiligand cell surface macromolecule which binds distinct ligands that accumulate in these settings. RAGE-ligand interaction evokes central changes in key biological properties of cells, including proliferation, generation of inflammatory mediators, and migration. Although RAGE-dependent signal transduction is critically dependent on its short cytoplasmic domain, to date the proximate mechanism by which this RAGE domain engages and stimulates cytoplasmic signaling pathways has yet to be identified. Here we show that the RAGE cytoplasmic domain interacts with Diaphanous-1 (Dia-1) both in vitro and in vivo. We employed the human RAGE cytoplasmic domain as "bait" in the yeast two-hybrid assay and identified the formin homology (FH1) domain of Dia-1 as a potential binding partner of this RAGE domain. Immunoprecipitation studies revealed that the RAGE cytoplasmic domain interacts with the FH1 domain of Dia-1. Down-regulation of Dia-1 expression by RNA interference blocks RAGE-mediated activation of Rac-1 and Cdc42 and, in parallel, RAGE ligand-stimulated cellular migration. Taken together, these findings indicate that the interaction of the RAGE cytoplasmic domain with Dia-1 is required to transduce extracellular environmental cues evoked by binding of RAGE ligands to their cell surface receptor, a chief consequence of which is Rac-1 and Cdc42 activation and cellular migration. Because RAGE and Dia-1 are implicated in the regulation of inflammatory, vascular, and transformed cell migration, these findings highlight this interaction as a novel target for therapeutic intervention in inflammation, atherosclerosis, diabetes, and cancer.
The benefits of endurance exercise on general health make it desirable to identify orally active agents that would mimic or potentiate the effects of exercise to treat metabolic diseases. Although certain natural compounds, such as reseveratrol, have endurance-enhancing activities, their exact metabolic targets remain elusive. We therefore tested the effect of pathway-specific drugs on endurance capacities of mice in a treadmill running test. We found that PPARbeta/delta agonist and exercise training synergistically increase oxidative myofibers and running endurance in adult mice. Because training activates AMPK and PGC1alpha, we then tested whether the orally active AMPK agonist AICAR might be sufficient to overcome the exercise requirement. Unexpectedly, even in sedentary mice, 4 weeks of AICAR treatment alone induced metabolic genes and enhanced running endurance by 44%. These results demonstrate that AMPK-PPARdelta pathway can be targeted by orally active drugs to enhance training adaptation or even to increase endurance without exercise.
Advanced glycosylation end products of proteins (AGEs) are nonenzymatically glycosylated proteins which accumulate in vascular tissue in aging and at an accelerated rate in diabetes. A approximately 35-kDa polypeptide with a unique NH2-terminal sequence has been isolated from bovine lung and found to be present on the surface of endothelial cells where it mediates the binding of AGEs (receptor for advanced glycosylation end product or RAGE). Using an oligonucleotide probe based on the amino-terminal sequence of RAGE, an apparently full-length cDNA of 1.5 kilobases was isolated from a bovine lung cDNA library. This cDNA encoded a 394 amino acid mature protein comprised of the following putative domains: an extracellular domain of 332 amino acids, a single hydrophobic membrane spanning domain of 19 amino acids, and a carboxyl-terminal domain of 43 amino acids. A partial clone encoding the human counterpart of RAGE, isolated from a human lung library, was found to be approximately 90% homologous to the bovine molecule. Based on computer analysis of the amino acid sequence of RAGE and comparison with databases, RAGE is a new member of the immunoglobulin superfamily of cell surface molecules and shares significant homology with MUC 18, NCAM, and the cytoplasmic domain of CD20. Expression of the RAGE cDNA in 293 cells allowed them to bind 125I-AGE-albumin in a saturable and dose-dependent manner (Kd approximately 100 nM), blocked by antibody to RAGE. Western blots of 293 cells transfected with RAGE cDNA probed with anti-RAGE IgG demonstrated expression of immunoreactive protein compared to its absence in mock-transfected cells. These results suggest that RAGE functions as a cell surface receptor for AGEs, which could potentially mediate cellular effects of this class of glycosylated proteins.
Though exercise training is part of most pulmonary rehabilitation programs, whether there is a physiologic basis for increased exercise tolerance is unclear. We sought to determine whether patients with chronic obstructive pulmonary disease (COPD) are capable of obtaining a physiologic training effect, as manifested by a reduction in blood lactate and ventilation (VE) at a given level of exercise. We also sought to determine whether training work rate determines the size of the training effect. Nineteen participants with COPD of predominantly moderate severity in an inpatient rehabilitation program performed two cycle ergometer exercise tests at a low and a high work rate for 15 min or to tolerance and also an incremental exercise test to tolerance. Arterial blood was sampled for blood gas and lactate analyses. Identical tests were performed before and after 5-day-per-week cycle ergometer training for 8 wk either for 45 min/day at a high work rate (average, 71 W) or for a proportionally longer time at a low work rate (average, 30 W). Average FEV1 was 56 +/- 12% predicted and did not change with training. Peak exercise lactate (average, 6.5 mEq/L) was not correlated with FEV1. For the high work rate training group, identical work rates engendered less lactate (4.5 versus 7.2 mEq/L) and less VE (48 versus 55 L/min) after training; the low work rate training group had significantly less lactate and VE decrease (p less than 0.01). Further, endurance time for the high constant work rate increased 73% in the high work rate training group but only 9% in the low work rate training group. At identical work rates, VE decrease average 2.5 L/min per mEq/L decrease in lactate (r = 0.75). We conclude that most COPD subjects studied increased blood lactate at low work rates. Many of these patients were able to achieve a physiologic training effect. Though total work was the same, training at a high work rate was more effective than was training at a low work rate. The lower VE requirement to perform exercise was in proportion to the lower lactate level, but the VE decrease for a given decrease in lactate was smaller than that seen in normal subjects (7.2 L/min/mEq/L), apparently because patients with COPD fall to hyperventilate in response to lactic acidosis (PaCO2 does not drop). These findings provide a physiologic rationale for exercise training of patients with COPD.
Nutritional depletion commonly occurs in patients with COPD, causing muscle wasting and impaired physiologic function. Two hundred seventeen patients with COPD participated in a placebo-controlled, randomized trial investigating the physiologic effects of nutritional intervention alone (N) for 8 wk or combined with the anabolic steroid nandrolone decanoate (N + A). Nandrolone decanoate or placebo (P) was injected intramuscularly (women, 25 mg; men, 50 mg) in a double-blind fashion on Days 1, 15, 29, and 43. Nutritional intervention consisted of a daily high caloric supplement (420 kcal; 200 ml). Also, all patients participated in an exercise program. In the depleted patients, both treatment regimens induced a similar significant body weight gain (2.6 kg) but different body compositional changes. Particularly in the last 4 wk of treatment, weight gain in the N group was predominantly due to an expansion of fat mass (p < 0.03 versus P and N + A), whereas the relative changes in fat-free mass (FFM) and other measures of muscle mass were more favorable in the N + A group (p < 0.03 versus P). Maximal inspiratory mouth pressure improved within both treatment groups in the first 4 wk of treatment, but after 8 wk only N + A was significantly different from P (p < 0.03). Nutritional supplementation in combination with a short course of anabolic steroids may enhance the gain in FFM and respiratory muscle function in depleted patients with COPD without causing adverse side effects.
The receptor for advanced glycation end products (RAGE), a newly-identified member of the immunoglobulin superfamily, mediates interactions of advanced glycation end product (AGE)-modified proteins with endothelium and other cell types. Survey of normal tissues demonstrated RAGE expression in situations in which accumulation of AGEs would be unexpected, leading to the hypothesis that under physiologic circumstances, RAGE might mediate interaction with ligands distinct from AGEs. Sequential chromatography of bovine lung extract identified polypeptides with M(r) values of approximately 12,000 (p12) and approximately 23,000 (p23) which bound RAGE. NH2-terminal and internal protein sequence data for p23 matched that reported previously for amphoterin. Amphoterin purified from rat brain or recombinant rat amphoterin bound to purified sRAGE in a saturable and dose-dependent manner, blocked by anti-RAGE IgG or a soluble form of RAGE (sRAGE). Cultured embryonic rat neurons, which express RAGE, displayed dose-dependent binding of 125I-amphoterin which was prevented by blockade of RAGE using antibody to the receptor or excess soluble receptor (sRAGE). A functional correlate of RAGE-amphoterin interaction was inhibition by anti-RAGE F(ab')2 and sRAGE of neurite formation by cortical neurons specifically on amphoterin-coated substrates. Consistent with a potential role for RAGE-amphoterin interaction in development, amphoterin and RAGE mRNA/antigen were co-localized in developing rat brain. These data indicate that RAGE has physiologically relevant ligands distinct from AGEs which are likely, via their interaction with the receptor, to participate in physiologic processes outside of the context of diabetes and accumulation of AGEs.
To compare the effects of comprehensive pulmonary rehabilitation with those of education alone on physiologic and psychosocial outcomes in patients with chronic obstructive pulmonary disease.
Randomized clinical trial.
University medical center.
119 outpatients with chronic obstructive pulmonary disease that was stable while patients received a standard medical regimen.
Patients were randomly assigned to either an 8-week comprehensive pulmonary rehabilitation program or to an 8-week education program. Pulmonary rehabilitation consisted of twelve 4-hour sessions that included education, physical and respiratory care instruction, psychosocial support, and supervised exercise training. Monthly reinforcement sessions were held for 1 year. The education group attended four 2-hour sessions that included video-tapes, lectures, and discussions but not individual instruction or exercise training.
Pulmonary function, maximum exercise tolerance and endurance, gas exchange, symptoms of perceived breathlessness and muscle fatigue with exercise, shortness of breath, self-efficacy for walking, depression, general quality of well-being, and hospitalizations associated with pulmonary diseases. Patients were followed for 6 years.
Compared with education alone, comprehensive pulmonary rehabilitation produced a significantly greater increase in maximal exercise tolerance (+1.5 metabolic equivalents [METS] compared with +0.6 METS [P < 0.001]; maximal oxygen uptake, +0.11 L/min compared with +0.03 L/min [P = 0.06]), exercise endurance (+10.5 minutes compared with +1.3 minutes [P < 0.001]), symptoms of perceived breathlessness (score of -1.5 compared with +0.2 [P < 0.001]) and muscle fatigue (score of -1.4 compared with -0.2 [P < 0.01]), shortness of breath (score of -7.0 compared with +0.6 [P < 0.01]), and self-efficacy for walking (score of +1.4 compared with +0.1 [P < 0.05]). There were slight but nonsignificant differences in survival (67% compared with 56% [P = 0.32]) and duration of hospital stay (-2.4 days/patient per year compared with +1.3 days/patient per year [P = 0.20]). Measures of lung function, depression, and general quality of life did not differ between groups. Differences tended to diminish after 1 year of follow-up.
Comprehensive pulmonary rehabilitation significantly improved exercise performance and symptoms for patients with moderate to severe chronic obstructive pulmonary disease. Benefits were partially maintained for at least 1 year and tended to diminish after that time.
In patients with chronic obstructive pulmonary disease exercise tolerance is commonly limited by breathlessness. These patients have an increased ventilatory load at rest which is exacerbated during exercise. The purpose of this study was to investigate the effect of supporting ventilation by non-invasive inspiratory pressure support (IPS) during submaximal treadmill exercise in such patients to see if they would experience less breathlessness and improve their exercise capacity.
Eight men with disabling breathlessness due to chronic obstructive pulmonary disease (COPD) (mean (SD) FEV1 0.73 (0.2) 1) were studied. Patients walked on a treadmill until their sensation of breathlessness, scored at one minute intervals, reached level 5 ("severe") on the 10-point Borg scale. Studies were performed with IPS (mean airway pressure 12-15 cm H2O), continuous positive airway pressure (CPAP 6 cm H2O), and with oxygen (2 l/min via a mask) in random order on three separate days. Each of these walks was compared with a control walk using a sham circuit (breathing air via an oxygen mask at 2 l/min from an unlabelled cylinder), and with a baseline walk in which patients walked freely on the treadmill. On cessation of exercise, distance achieved and a leg fatigue score were recorded.
No patients stopped due to leg fatigue, all stopping only when their sensation of breathlessness had reached level 5 on the Borg scale. IPS improved median walking distance by 62% compared with the control walk (sham circuit). There was no change in walking distance with either CPAP or oxygen at 2 l/min. There was no difference between the control and the baseline walks.
Inspiratory pressure support can reduce breathlessness and increase exercise tolerance to submaximal treadmill exercise in patients with COPD. This could have implications for the rehabilitation of these severely disabled patients.
Prevalence and characteristics of nutritional depletion were established by body composition measurements in 255 COPD patients in stable clinical condition admitted to a pulmonary rehabilitation center. Depletion of body weight, fat-free mass (using bioelectrical resistance measurements), and muscle mass [from creatinine height index (CHI) and midarm muscle circumference] was most pronounced (40 to 50%) in patients suffering from chronic hypoxemia and in normoxemic patients with severe airflow obstruction (FEV1 < 35%) but also occurred in +/- 25% of patients with moderate airflow obstruction. Classification of the patients in four groups by body weight and fat-free mass revealed that depletion of fat-free mass may occur in normal-weight COPD patients (Group 3). These patients also exhibit a decreased CHI (61 +/- 21%, mean +/- SD) and suffer from physical impairment (12-min walking distance, WD, 532 +/- 152 m) to an even greater degree than underweight patients with relative preservation of fat-free mass (Group 2) (CHI = 73 +/- 16%; WD = 744 +/- 233 m). No systematic differences were established between the four groups in serum protein concentrations or medication use. We conclude that fat-free mass is a better indicator of body mass depletion than body weight. Classification of COPD patients by body weight and fat-free mass may have consequences for planning and interpretation of intervention strategies, particularly in Group 2 and 3 patients.
Patients with chronic obstructive pulmonary disease (COPD) often develop weight loss, which is associated with increased mortality. Recombinant human growth hormone (rhGH) treatment has been proposed to improve nitrogen balance and to increase muscle strength in these patients. The aim of this study was to assess the effects of rhGH administration on the nutritional status, resting metabolism, muscle strength, exercise tolerance, dyspnea, and subjective well-being of underweight patients with stable COPD. Sixteen patients attending a pulmonary rehabilitation program (age: 66 +/- 9 yr; weight: 77 +/- 7% of ideal body weight; FEV1: 39 +/- 13% of predicted) were randomly treated daily with either 0.15 IU/kg rhGH or placebo during 3 wk in a double-blind fashion. Measurements were made at the beginning (DO) and at the end (D21) of treatment and 2 mo later (D81). Body weight was similar in the two groups during the study, but lean body mass was significantly higher in the rhGH group at D21 (p < 0.01) and D81 (p < 0.05). The increase in lean body mass was 2.3 +/- 1.6 kg in the rhGH group and 1.1 +/- 0.9 kg in the control group at D21 and 1.9 +/- 1.6 kg in the rhGH group and 0.7 +/- 2.1 kg in the control group at D81. At D21, the resting energy expenditure was increased in the rhGH group (107.8% of DO, p < 0.001 compared with the control group). At D21 and D81, the changes in maximal respiratory pressures, handgrip strength, maximal exercise capacity, and subjective well-being were similar in the two groups. At D21, the 6-min walking distance decreased in the rhGH group (-13 +/- 31%) and increased in the control group (+10 +/- 14%; p < 0.01). We conclude that the daily administration of 0.15 IU/kg rhGH during 3 wk increases lean body mass but does not improve muscle strength or exercise tolerance in underweight patients with COPD.
To evaluate the influence of oral anabolic steroids on body mass index (BMI), lean body mass, anthropometric measures, respiratory muscle strength, and functional exercise capacity among subjects with COPD.
Prospective, randomized, controlled, double-blind study.
Pulmonary rehabilitation program.
Twenty-three undernourished male COPD patients in whom BMI was below 20 kg/m2 and the maximal inspiratory pressure (PImax) was below 60% of the predicted value.
The study group received 250 mg of testosterone i.m. at baseline and 12 mg of oral stanozolol a day for 27 weeks, during which time the control group received placebo. Both groups participated in inspiratory muscle exercises during weeks 9 to 27 and cycle ergometer exercises during weeks 18 to 27.
Seventeen of 23 subjects completed the study. Weight increased in nine of 10 subjects who received anabolic steroids (mean, +1.8+/-0.5 kg; p<0.05), whereas the control group lost weight (-0.4+/-0.2 kg). The study group's increase in BMI differed significantly from that of the control group from weeks 3 to 27 (p<0.05). Lean body mass increased in the study group at weeks 9 and 18 (p<0.05). Arm muscle circumference and thigh circumference also differed between groups (p<0.05). Changes in PImax (study group, 41%; control group, 20%) were not statistically significant. No changes in the 6-min walk distance or in maximal exercise capacity were identified in either group.
The administration of oral anabolic steroids for 27 weeks to malnourished male subjects with COPD was free of clinical or biochemical side effects. It was associated with increases in BMI, lean body mass, and anthropometric measures of arm and thigh circumference, with no significant changes in endurance exercise capacity.
Slow- and fast-twitch myofibers of adult skeletal muscles express unique sets of muscle-specific genes, and these distinctive programs of gene expression are controlled by variations in motor neuron activity. It is well established that, as a consequence of more frequent neural stimulation, slow fibers maintain higher levels of intracellular free calcium than fast fibers, but the mechanisms by which calcium may function as a messenger linking nerve activity to changes in gene expression in skeletal muscle have been unknown. Here, fiber-type-specific gene expression in skeletal muscles is shown to be controlled by a signaling pathway that involves calcineurin, a cyclosporin-sensitive, calcium-regulated serine/threonine phosphatase. Activation of calcineurin in skeletal myocytes selectively up-regulates slow-fiber-specific gene promoters. Conversely, inhibition of calcineurin activity by administration of cyclosporin A to intact animals promotes slow-to-fast fiber transformation. Transcriptional activation of slow-fiber-specific transcription appears to be mediated by a combinatorial mechanism involving proteins of the NFAT and MEF2 families. These results identify a molecular mechanism by which different patterns of motor nerve activity promote selective changes in gene expression to establish the specialized characteristics of slow and fast myofibers.
S100/calgranulin polypeptides are present at sites of inflammation, likely released by inflammatory cells targeted to such loci by a range of environmental cues. We report here that receptor for AGE (RAGE) is a central cell surface receptor for EN-RAGE (extracellular newly identified RAGE-binding protein) and related members of the S100/calgranulin superfamily. Interaction of EN-RAGEs with cellular RAGE on endothelium, mononuclear phagocytes, and lymphocytes triggers cellular activation, with generation of key proinflammatory mediators. Blockade of EN-RAGE/RAGE quenches delayed-type hypersensitivity and inflammatory colitis in murine models by arresting activation of central signaling pathways and expression of inflammatory gene mediators. These data highlight a novel paradigm in inflammation and identify roles for EN-RAGEs and RAGE in chronic cellular activation and tissue injury.
Objective: To examine the short- and long-term effects of an outpatient pulmonary rehabilitation program for COPD patients on dyspnea, exercise, health-related quality of life, and hospitalization rate. Setting: Secondary-care respiratory clinic in Barcelona. Methods: We conducted a randomized controlled trial with blinding of outcome assessment and follow-up at 3, 6, 9, 12, 18, and 24 months. Sixty patients with moderate to severe COPD (age 65 6 7 years; FEV1 35 6 14%) were recruited. Thirty patients randomized to rehabilitation received 3 months of outpatient breathing retraining and chest physiotherapy, 3 months of daily supervised exercise, and 6 months of weekly supervised breathing exercises. Thirty patients randomized to the control group received standard care. Results: We found significant differences between groups in perception of dyspnea (p < 0.0001), in 6-min walking test distance (p < 0.0001), and in day-to-day dyspnea, fatigue, and emotional function measured by the Chronic Respiratory Questionnaire (p < 0.01). The improvements were evident at the third month and continued with somewhat diminished magnitude in the second year of follow-up. The PR group experienced a significant (p < 0.0001) reduction in exacerbations, but not the number of hospitalizations. The number of patients needed to treat to achieve significant benefit in health-related quality of life for a 2-year period was approximately three. Conclusion: Outpatient rehabilitation programs can achieve worthwhile benefits that persist for a period of 2 years. (CHEST 2000; 117:976 ‐983)
Administration of supplemental oxygen significantly improved exercise tolerance in patients with chronic obstructive pulmonary disease. This was achieved by a reduction of ventilatory requirements for the same work load, such that limiting ventilatory capacity was not achieved until later in incremental work. Breathing supplemental oxygen produced lower levels of lactate, but relief of anaerobiasis did not contribute to ventilatory changes, since potential acid-base alterations were balanced by concomitant retention of carbon dioxide.
Study objectives
Skeletal muscle weakness commonly occurs in patients with COPD. Long-term use of systemic glucocorticosteroids further contributes to muscle weakness. Anabolic steroids could be an additional mode of intervention to improve outcome of pulmonary rehabilitation by increasing physiologic functioning, possibly mediated by increasing erythropoietic function.
Patients and methods
We randomly assigned 63 male patients with COPD to receive on days 1, 15, 29, and 43 a deep IM injection of 50 mg of nandrolone decanoate (ND) [Deca-Durabolin; N.V. Organon; Oss, The Netherlands] in 1 mL of arachis oil, or 1 mL of arachis oil alone (placebo) in a double-blind design. All patients participated in a standardized pulmonary rehabilitation program. Outcome measures were body composition by deuterium and bromide dilution, respiratory and peripheral muscle function, incremental exercise testing, and health status by the St. George’s Respiratory Questionnaire.
Results
Treatment with ND relative to placebo resulted in higher increases in fat-free mass (FFM; mean, 1.7 kg [SD, 2.5] vs 0.3 kg [SD, 1.9]; p = 0.015) owing to a rise in intracellular mass (mean, 1.8 kg [SD, 3.1] vs – 0.5 kg [SD, 3.1]; p = 0.002). Muscle function, exercise capacity, and health status improved in both groups to the same extent. Only after ND were increases in erythropoietic parameters seen (erythropoietin: mean, 2.08 U/L [SD, 5.56], p = 0.067; hemoglobin: mean, 0.29 mmol/L [SD, 0.73], p = 0.055). In the total group, the changes in maximal inspiratory mouth pressure (Pimax) and peak workload were positively correlated with the change in hemoglobin (r = 0.30, p = 0.032, and r = 0.34, p = 0.016, respectively), whereas the change in isokinetic leg work was correlated with the change in erythropoietin (r = 0.38, p = 0.013). In the patients receiving maintenance treatment with low-dose oral glucocorticosteroids (31 of 63 patients; mean, 7.5 mg/24 h [SD, 2.4]), greater improvements in Pimax (mean, 6.0 cm H2O [SD, 8.82] vs – 2.18 cm H2O [SD, 11.08], p = 0.046), and peak workload (mean, 20.47 W [SD, 19.82] vs 4.80 W [SD, 7.74], p = 0.023) were seen after 8 weeks of treatment with ND vs placebo.
Conclusions
In conclusion, a short-term course of ND had an overall positive effect relative to placebo on FFM without expanding extracellular water in patients with COPD. In the total group, the improvements in muscle function and exercise capacity were associated with improvements in erythropoietic parameters. The use of low-dose oral glucocorticosteroids as maintenance medication significantly impaired the response to pulmonary rehabilitation with respect to respiratory muscle function and exercise capacity, which could be restored by ND treatment.
Inadequate physical activity is linked to many chronic diseases. But the mechanisms that tie muscle activity to health are unclear. The transcriptional coactivator PGC1 has recently been shown to regulate several exercise-associated aspects of muscle function. We propose that this protein controls muscle plasticity, suppresses a broad inflammatory response and mediates the beneficial effects of exercise.
Aims:
The receptor for advanced glycation end-products (RAGE) has been implicated in diabetic microvascular complications, but several lines of evidence suggest that the soluble isoform of RAGE (sRAGE) may protect against AGE-mediated vessel damage. The characterized AGE Nepsilon-carboxymethyllysine (CML) is associated with diabetic microvascular complications. In the present study, we measured blood levels of sRAGE and CML-protein in diabetic patients with and without microvascular complications.
Methods:
Thirty patients with type-2 diabetes were recruited into the study, comprising 20 who had no microvascular complications, and 10 who had both retinal and renal complications. sRAGE was measured in serum by ELISA, and CML by competitive ELISA.
Results:
sRAGE blood levels were similar in both the controls and diabetic patients without microvascular complications. In patients with complications, the mean sRAGE blood level was significantly decreased (1068+/-231pg/mL) compared with diabetic patients without complications (P=0.028). CML-protein was increased in all diabetic patients, but to a higher extent in those who had microvascular complications.
Conclusion:
The association of low sRAGE with high CML-protein levels in diabetic patients who developed severe diabetic complications supports the hypothesis that sRAGE protects vessels against AGE-mediated diabetic microvascular damage.
The interaction of glucose-modified and inflammation-promoting ligands with the receptor for advanced glycation end products (RAGE) is emerging as a central mechanism contributing to the diverse complications of diabetes. These ligands, particularly in oligomeric form, bind to RAGE and transduce intracellular signals. The consequences of this interaction, as elucidated in cultured cells and animal models, include upregulation of inflammatory and tissue-degradative pathways. Pharmacologic antagonism of RAGE may hold promise for the treatment of diabetic complications.
Insulin-like growth factor I (IGF-I) peptide levels have been shown to increase in overloaded skeletal muscles (G. R. Adams and F. Haddad. J. Appl. Physiol. 81: 2509-2516, 1996). In that study, the increase in IGF-I was found to precede measurable increases in muscle protein and was correlated with an increase in muscle DNA content. The present study was undertaken to test the hypothesis that direct IGF-I infusion would result in an increase in muscle DNA as well as in various measurements of muscle size. Either 0.9% saline or nonsystemic doses of IGF-I were infused directly into a non-weight-bearing muscle of rats, the tibialis anterior (TA), via a fenestrated catheter attached to a subcutaneous miniosmotic pump. Saline infusion had no effect on the mass, protein content, or DNA content of TA muscles. Local IGF-I infusion had no effect on body or heart weight. The absolute weight of the infused TA muscles was approximately 9% greater (P < 0.05) than that of the contralateral TA muscles. IGF-I infusion resulted in significant increases in the total protein and DNA content of TA muscles (P < 0.05). As a result of these coordinated changes, the DNA-to-protein ratio of the hypertrophied TA was similar to that of the contralateral muscles. These results suggest that IGF-I may be acting to directly stimulate processes such as protein synthesis and satellite cell proliferation, which result in skeletal muscle hypertrophy.
Advanced glycation end-products (AGEs) and the receptor for AGEs (RAGE) system plays an important role in the development of atherosclerosis. It has been recently reported that endogenous secretory RAGE (esRAGE) and total soluble RAGE (sRAGE) levels are associated with diabetic complications. The aim of the present study is to longitudinally evaluate the association between esRAGE and sRAGE levels and the progression of carotid intima-media thickness (IMT), a surrogate marker of atherosclerosis.
Japanese type 1 diabetic patients (n=47, aged 24.0+/-3.1 years) were enrolled into a 4-year follow-up study and annual measurements of serum esRAGE and sRAGE levels and IMTs were performed. At baseline, mean-IMT was inversely correlated with circulating esRAGE levels (r=-0.317, p=0.0292), whereas there was not statistical significance between mean-IMT and sRAGE levels. Mean-IMT significantly increased during the follow-up period (from 0.63+/-0.10 to 0.67+/-0.10mm, p=0.0022). Annual increase in mean-IMT (=(mean-IMT after 4 years-mean-IMT at baseline)/4) was positively correlated with the arithmetic average of systolic blood pressure (r=0.310, p=0.0332) and triglyceride (r=0.337, p=0.0201), and inversely correlated with circulating esRAGE levels (r=-0.360, p=0.0124) and sRAGE levels (r=-0.406, p=0.0042) during the follow-up period. Furthermore, stepwise multivariate regression analyses revealed that continuous low levels of circulating esRAGE and sRAGE were determinants of the progression of mean-IMT independently of conventional risk factors.
Circulating esRAGE level as well as sRAGE level was an independent risk factor for the progression of carotid IMT in type 1 diabetic subjects.
In patients with chronic obstructive pulmonary disease (COPD) and hyperinflation of the lungs, dysfunction of the diaphragm may contribute to respiratory decompensation. We evaluated the contractile function of the diaphragm in well-nourished patients with stable COPD, using supramaximal, bilateral phrenic-nerve stimulation, which provides information about the strength and inspiratory action of the diaphragm.
In eight patients with COPD and five control subjects of similar age, the transdiaphragmatic pressure generated by the twitch response to phrenic-nerve stimulation was recorded at various base-line lung volumes, from functional residual capacity to total lung capacity, and during relaxation and graded voluntary efforts at functional residual capacity (twitch occlusion).
At functional residual capacity, the twitch transdiaphragmatic pressure ranged from 10.9 to 26.6 cm of water (1.07 to 2.60 kPa) in the patients and from 19.8 to 37.1 cm of water (1.94 to 3.64 kPa) in the controls, indicating considerable overlap between the two groups. The ratio of esophageal pressure to twitch transdiaphragmatic pressure, an index of the inspiratory action of the diaphragm, was -0.50 +/- 0.05 in the patients, as compared with -0.43 +/- 0.02 in the controls (indicating more efficient inspiratory action in the patients than in the controls). At comparable volumes, the twitch transdiaphragmatic pressure and esophageal-to-transdiaphragmatic pressure ratio were higher in the patients than in normal subjects, indicating that the strength and inspiratory action of the diaphragm in the patients were actually better than in the controls. Twitch occlusion (a measure of the maximal activation of the diaphragm) indicated near-maximal activation in the patients with COPD, and the maximal transdiaphragmatic pressure was 106.9 +/- 13.8 cm of water (10.48 +/- 1.35 kPa).
The functioning of the diaphragms of the patients with stable COPD is as good as in normal subjects at the same lung volume. Compensatory phenomena appear to counterbalance the deleterious effects of hyperinflation on the contractility and inspiratory action of the diaphragm in patients with COPD. Our findings cast doubt on the existence of chronic fatigue of the diaphragm in such patients and therefore on the need for therapeutic interventions aimed at improving diaphragm function.
We carried out a prospective randomized controlled trial to investigate the effects of short-term refeeding (16 days) in 10 malnourished inpatients with chronic obstructive pulmonary disease (COPD). Six patients were randomized to receive sufficient nasoenterically administered calories to provide a total caloric intake equal to 1,000 kcal above their usual intake. The other four patients were sham fed, receiving only 100 kcal more. Measurements of nutritional status, respiratory muscle strength and endurance, adductor pollicis function, and pulmonary function were performed initially and at study end. The refed group gained significantly more weight and showed significant increases in maximal expiratory pressure and mean sustained inspiratory pressure. There were no significant changes in the maximal inspiratory pressure or in adductor pollicis function. In malnourished inpatients with COPD, short-term refeeding leads to improvement in respiratory muscle endurance and in some parameters of respiratory muscle strength in the absence of demonstrable changes in peripheral muscle function.
To determine the effect of moderate dietary sodium restriction on the hypertension of non-insulin-dependent (type II) diabetes.
Randomised parallel controlled study of moderate sodium restriction for three months compared with usual diabetic diet, followed by randomised double blind crossover trial of sustained release preparation of sodium for one month versus placebo for one month in patients continuing with sodium restriction.
Patients attending diabetic outpatient clinic of city hospital.
Thirty four patients with established type II diabetes complicated by mild hypertension (systolic blood pressure greater than 160 mm Hg or diastolic pressure greater than 95 mm Hg on three consecutive occasions). Patients already taking antihypertensive agents (but not diuretics) not barred from study provided that criteria for mild hypertension still met. Conditions precluding patients from study were diabetic or hypertensive nephropathy, cardiac failure, and pregnancy.
After run in phase with recordings at seven weeks, three weeks, and time zero patients were allocated at random to receive moderate dietary sodium restriction for three months (n = 17) or to continue with usual diabetic diet. Subsequently nine patients in sodium restriction group continued with regimen for a further two months, during which they completed a randomised double blind crossover trial of sustained release preparation of sodium (Slow Sodium 80 mmol daily) for one month versus matching placebo for one month.
Reduction in blood pressure in type II diabetics with mild hypertension.
Supine and erect blood pressure, body weight, and 24 hour urinary sodium and potassium excretion measured monthly during parallel group and double blind crossover studies. After parallel group study sodium restriction group showed significant reduction in systolic blood pressure (supine 19.2 mm Hg, erect 21.4 mm Hg; p less than 0.001) and mean daily urinary sodium excretion (mean reduction 60 mmol/24 h). There were no appreciable changes in weight, diabetic control, or diastolic pressure. No significant changes occurred in controls. In double blind crossover study mean supine systolic blood pressure rose significantly (p less than 0.005) during sodium supplementation (to 171 mm Hg) compared with value after three months of sodium restriction alone (159.9 mm Hg) and after one month of placebo (161.8 mm Hg).
Moderate dietary restriction of sodium has a definite hypotensive effect, which may be useful in mild hypertension of type II diabetes.
Administration of supplemental oxygen significantly improved exercise tolerance in patients with chronic obstructive pulmonary disease. This was achieved by a reduction of ventilatory requirements for the same work load, such that limiting ventilatory capacity was not achieved until later in incremental work. Breathing supplemental oxygen produced lower levels of lactate, but relief of anaerobiasis did not contribute to ventilatory changes, since potential acid-base alterations were balanced by concomitant retention of carbon dioxide.
We examined the effect of a 6-wk exercise training program on several skeletal enzymes in patients with chronic obstructive pulmonary disease. Eight trained their arms and 7 trained their legs. In all patients, muscle biopsy specimens were taken from the trained limbs, and in 7 patients, additional biopsy specimens were taken from the untrained limbs. The enzymes examined were citrate synthase, 3-beta-hydroxyacyl coenzyme A dehydrogenase, and pyruvate kinase. Also examined were cardiac frequency responses to incremental and endurance cycle ergometry; these responses were evaluated for arm and leg exercise, respectively. Despite the patient's increased exercise endurance, we were unable to document a significant increase in the enzyme concentrations in the trained limbs. Similarly, analyses of the cardiac frequency failed to show the evolution of the typical cardiovascular training response. This pattern is in marked contrast to that seen in normal subjects after endurance training. We conclude that patients with chronic obstructive pulmonary disease are incapable of exercising at an intensity high enough to induce the classic training response and associated changes in muscle enzymes. Therefore, other mechanisms must be important in explaining the increased endurance for submaximal exercise.
Reduced diaphragm contractility has been described in normal subjects after whole body endurance exercise, and it indicates low frequency fatigue (LFF); it is unknown whether LFF is of clinical importance. We therefore studied the effect of treadmill exercise to exhaustion on diaphragm contractility in six patients with severe chronic obstructive pulmonary disease (COPD) (mean FEV1, 0.71, 27% predicted). The subjects first performed a short (control), treadmill walk and then, after resting, a second walk to a state of severe dyspnea. Cervical magnetic stimulation of the phrenic nerve roots was performed at the start of the study and 20 and 30 min after each walk. The twitch transdiaphragmatic pressure (Tw Pdi) was reproducible (mean coefficient of variation, 5.3%; range, 2 to 12.5%). Mean Twi Pdis were 18.4 cm H2O at baseline and 19.6 cm H2O and 19.2 cm H2O 20 and 30 min after the control walk. At the same times after the exhaustive walk, mean Tw Pdis were 19.6 and 20.4 cm H20. Tw Pdi was not reduced by exhaustive treadmill walking (p > 0.9), and a power calculation showed that the study had a 95% chance of detecting a 10% fall at the 5% significance level. We conclude that Tw Pdi is not reduced when patients with severe COPD walk to a state of extreme breathlessness and that therefore low frequency fatigue of the diaphragm does not occur.
Exercise training has been of limited success in patients with severe chronic airflow obstruction (CAO), in part because of the reduced ventilatory capacity and excessive dyspnea experienced. Pressure support (PS) is a new form of mechanical ventilation which can effectively assist ventilation when applied noninvasively to patients in acute respiratory failure. It was hypothesized that PS might also be used to improve exercise performance, and ultimately physical conditioning, in ambulatory patients with CAO undergoing exercise training. To begin to address this concept, the objectives of the present study were (1) to examine the feasibility of providing PS to exercising patients with CAO and (2) to determine its effects on breathing pattern, inspiratory effort, and dyspnea. Flow and volume, mouth, esophageal, and gastric pressure were measured in seven patients with severe CAO (mean FEV1 = 0.75 +/- SEM 0.09 L) performing constant workload bicycle exercise (33 +/- 6 watts) during control conditions and with the application of PS (approximately 10 cm H2O). PS increased minute ventilation as a result of changes in both tidal volume and respiratory rate. This occurred despite marked reductions in inspiratory effort, as indicated by the pressure-time integrals of esophageal (68 +/- 5% control, p < 0.0005) and transdiaphragmatic pressure (52 +/- 8% control, p < 0.0005). Using a 5-point bidirectional scale to assess changes in dyspnea, breathlessness improved significantly with the addition of PS (2.3 +/- 0.6, p < 0.05) and worsened to a similar degree when it was removed (2.1 +/- 0.5, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
To assess physiologic effects of continuous positive airway pressure (CPAP) and positive end-expiratory pressure (PEEP) during noninvasive pressure support ventilation (PSV) in patients with acute exacerbation of chronic obstructive pulmonary disease (COPD), we measured in seven patients the breathing pattern, lung mechanics, diaphragmatic effort (PTPdi), and arterial blood gases under four conditions: (1) spontaneous breathing (SB); (2) CPAP; (3) PSV of 10 cm H2O; and (4) PSV plus PEEP (PEEP + PSV). CPAP and PEEP were set between 80 and 90% of dynamic intrinsic PEEP (PEEPidyn) measured during SB and PSV, respectively. PEEPidyn was obtained (1) from the decrease in pleural pressure (delta Ppl) preceding inspiration, and (2) subtracting the fall in gastric pressure (delta Pga) caused by relaxation of the abdominal muscles from the delta Ppl decrease. Abdominal muscle activity made PEEPidyn overestimated in almost all instances (p < 0.0001). PSV increased minute ventilation, improved gas exchange, and decreased PTPdi. PEEP added to PSV, likewise CPAP compared with SB, further significantly decreased the diaphragmatic effort (PTPdi went from 322 +/- 111 to 203 +/- 63 cm H2O.s) by counterbalancing PEEPidyn, which went from 5.4 +/- 4.0 to 3.1 +/- 2.3 cm H2O. These data support the use of low levels of PEEP (80 to 90% of PEEPidyn) to treat acute exacerbation of COPD by means of mask PSV.
We studied the effects of ingesting an antioxidant vitamin mixture for 6 wk on breath pentane and serum malondialdehyde (MDA) levels before and after exercise. Twenty young (mean age 25.0 +/- 2.9 yr) healthy males were randomly assigned to either an antioxidant vitamin group (daily doses of 592 mg of alpha-tocopherol equivalents, 1,000 mg of ascorbic acid, and 30 mg of beta-carotene) or a placebo group. Exercise consisted of 30 min of treadmill running at 60% of maximal O2 consumption (VO2max) followed by 5 min of running at a pace that elicited approximately 90% of VO2max. Blood and breath samples were collected immediately after the two exercise bouts. The antioxidant supplement did not prevent the exercise-induced increase in lipid peroxidation, as reflected by the rate of pentane production and the increase in serum MDA concentration. However, ingestion of the antioxidant vitamins did result in significantly lower resting and postexercise levels of expired pentane and serum MDA. We conclude that taking ascorbate, alpha-tocopherol, and beta-carotene in the amounts used in this study serves to lower markers of lipid peroxidation at rest and after exercise but does not prevent the exercise-induced increase in oxidative stress.
Dynamic hyperinflation (DH) is a major pathophysiologic consequence of airflow limitation during exercise in patients with chronic obstructive pulmonary disease (COPD) and an important contributing factor to breathlessness. In this study we aimed to examine the effect of inhaled beta agonist therapy on DH during exercise in these patients and the relationship between changes in DH and breathlessness. In 13 COPD patients (mean age 65.1 +/- 2.0, FEV1 1.20 +/- 0.17, FEV1/FVC 40 +/- 3) we measured pulmonary function tests, exercise breathlessness by Borg score, and exercise flow volume and pressure volume loops on two separate days. Prior to testing, patients randomly received inhaled placebo or albuterol on the first test day and the alternative medication on the second test day. From measurements of exercise inspiratory capacity (IC), we calculated the end-expiratory and end-inspiratory lung volumes (EELV, EILV). We used esophageal pressure recordings to measure peak inspiratory esophageal pressure (Pesins) during exercise and this was related to the maximal capacity for pressure generation taking into account lung volume and airflow changes (Pcapi). Bronchodilator caused significant increase in both FEV1 and FVC (+0.23 and +0.51, p<0.01). Comparisons of breathlessness, exercise volumes, and pressures were made at the highest equivalent work load. There was a significant reduction in the peak exercise EELV/TLC (80 +/- 0.02% to 76 +/- 0.02%, p<0.05) while the peak EILV/TLC decreased by 2% (97 +/- 1% to 95 +/- 1%, p<0.05). The peak Pesins/Pcapi decreased (0.79 +/- 0.10 to 0.57 +/- 0.05, p<0.05), and the Pcapi - Pesins increased (7.4 +/- 3 to 13.0 +/- 3 cm H2O, p<0.05). There was significant improvement in neuroventilatory coupling for volume change (Pesins/Pcapi/VT/TLC 5.45 +/- 0.5 to 3.25 +/- 1.0, p<0.05). There was a significant reduction in breathlessness as measured by Borg score (4.5 +/- 0.7 to 3.1 +/- 0.5, p<0.05) and there was a significant correlation between delta Borg and delta EILV/TLC (r=0.771, p<0.01) with a trend for Pesins/Pcapi/VT/TLC (r=0.544, p=0.067). There was also a significant correlation between delta EELV/TLC and delta Pesins/Pcapi/VT/TLC (r=0.772, p<0.01). The relationships between delta Borg, delta resting volumes, and flow rates were not significant. We conclude that in patients with COPD, inhaled bronchodilator reduces exercise DH and improves inspiratory pressure reserve and neuroventilatory coupling. Changes in DH and neuroventilatory coupling were the main determinants of reduced breathlessness.
The purpose of this study was to evaluate the physiologic responses to endurance training in patients with moderate to severe airflow obstruction by specifically looking at changes in skeletal muscle enzymatic activities. Eleven patients (age = 65 +/- 7 yr, mean +/- SD, FEV1 = 36 +/- 11% of predicted value, range = 24 to 54%) were evaluated before and after an endurance training program. Each evaluation included a percutaneous biopsy of the vastus lateralis and a stepwise exercise test on an ergocycle up to his/her maximal capacity. VE, VO2, VcO2, and serial arterial lactic acid concentration were measured during the exercise test. The activity of two oxidative enzymes, citrate synthase (CS) and 3-hydroxyacyl-CoA dehydrogenase (HADH), and of three glycolytic enzymes, lactate dehydrogenase, hexokinase, and phosphofructokinase was determined. The training consisted of 30-min exercise sessions on a calibrated ergocycle, 3 times a week for 12 wk. The aerobic capacity was severely reduced at baseline (VO2max = 54 +/- 12% of predicted) and increased by 14% after training (p < 0.05). For an identical exercise workload, there was a significant reduction in VE (34.5 +/- 10.0 versus 31.9 +/- 9.0 L/min, p < 0.05) and in arterial lactic acid concentration (3.4 +/- 1.3 versus 2.8 +/- 0.9 mmol/L, p < 0.01) after training. The lactate threshold also increased after training (p < 0.01) while the activity of the three glycolytic enzymes was similar at the two evaluations. In contrast, the activity of CS and HADH increased significantly after training (22.3 +/- 3.5 versus 25.8 +/- 3.8 mumol/min/g muscle for CS, p < 0.05, and 5.5 +/- 2.9 versus 7.7 +/- 2.5 mumol/min/g for HADH, p < 0.01). A significant inverse relationship was found between the percent changes in the activity of CS and HADH, and the percent changes in arterial lactic acid during exercise (p = 0.01). We conclude that endurance training can reduce exercise-induced lactic acidosis and improve skeletal muscle oxidative capacity in patients with moderate to severe chronic obstructive pulmonary disease (COPD).
The mechanisms of exertional dyspnea relief in response to supplemental oxygen (O2) in chronic airflow limitation (CAL) are not precisely known and are likely multifactorial. To explore factors contributing to the relief of dyspnea after oxygen administration, 11 patients with severe CAL (FEV1.0 = 39 +/- 3% predicted, mean +/- SEM) and mild hypoxemia (resting PaO2 = 74 +/- 2 mm Hg) breathed room air (RA) and 60% O2 during exercise at approximately 50% of their maximal incremental exercise capacity. Breathlessness ratings (Borg scale), endurance time, respiratory drive (change in mouth occlusion pressure over the first 0.1 s of inspiration, P0.1), ventilation (VE), breathing pattern, operational lung volumes, gas exchange, and metabolic parameters were compared during RA and 60% O2. PaO2 at exercise cessation during RA and 60% O2 was 65 +/- 3 mm Hg and 226 +/- 12 mm Hg, respectively (p < 0.001). With 60% O2, the mean of individual Borg/time slopes fell significantly (p < 0.05) by 23 +/- 12% and was associated with a 35 +/- 11% increase (p < 0.01) in endurance time (r = -0.64, p < 0.05). During 60% O2, slopes of P0.1 and lactate over time also fell significantly (p < 0.05), whereas delta PaCO2/time did not change significantly. At a standardized time near end-exercise, Borg, VE, and P0.1 changed during 60% O2 by -0.8 +/- 0.3 (p < 0.05), -4.1 +/- 2.0 L/min (p = 0.07), and -1.3 +/- 0.5 cm H2O/s (p < 0.05), respectively. Slopes of Borg/VE, Borg/lactate, and VE/lactate were essentially superimposable during tests on RA and O2: Borg, lactate, and VE all fell proportionally during hyperoxia. In patients with CAL and mild exercise hypoxemia, relief of exertional breathlessness during hyperoxia is explained by reduced ventilatory demand in association with reduced blood lactate levels.
In patients with severe chronic obstructive pulmonary disease, the diaphragm undergoes physiologic adaptations characterized by an increase in energy expenditure and relative resistance to fatigue. We hypothesized that these physiologic characteristics would be associated with structural adaptations consisting of an increased proportion of less-fatigable slow-twitch muscle fibers and slow isoforms of myofibrillar proteins.
We obtained biopsy specimens of the diaphragm from 6 patients with severe chronic obstructive pulmonary disease (mean [+/-SE] forced expiratory volume in one second, 33+/-4 percent of the predicted value; residual volume, 259+/-25 percent of the predicted value) and 10 control subjects. The proportions of the various isoforms of myosin heavy chains, myosin light chains, troponin, and tropomyosin were determined by sodium dodecyl sulfate-polyacrylamide-gel electrophoresis. We also used immunocytochemical techniques to determine the proportions of the various types of muscle fibers.
The diaphragm-biopsy specimens from the patients had higher percentages of slow myosin heavy chain I (64+/-3 vs. 45+/-2 percent, P<0.001), and lower percentages of fast myosin heavy chains IIa (29+/-3 vs. 39+/-2 percent, P=0.01) and IIb (8+/-1 vs. 17+/-1 percent, P<0.001) than the diaphragms of the controls. Similar differences were noted when immunohistochemical techniques were used to compare the percentages of these fiber types in the two groups. In addition, the patients had higher percentages of the slow isoforms of myosin light chains, troponins, and tropomyosin, whereas the controls had higher percentages of the fast isoforms of these proteins.
Severe chronic obstructive pulmonary disease increases the slow-twitch characteristics of the muscle fibers in the diaphragm, an adaptation that increases resistance to fatigue.
We studied the impact of a 6-wk supervised, multimodality endurance exercise training program (EXT) on strength and endurance of ventilatory and peripheral muscles in patients with chronic airflow limitation (CAL), and determined whether potential improvements contributed to relief of exertional breathlessness (B) and perceived leg effort/discomfort (LE), respectively. Twenty breathless patients with stable CAL (FEV1 = 41 +/- 3% predicted; mean +/- SEM) were tested at 6-wk intervals at baseline, after a nonintervention control period (pre-EXT), and post-EXT. Measurements included: pulmonary function tests (PFTs), maximal inspiratory/expiratory pressures (MIP, MEP), inspiratory muscle endurance (V(LIM)), quadriceps strength and endurance, exercise endurance, and submaximal cycle exercise with cardioventilatory and symptom responses. Measurements at baseline and pre-EXT were identical. Post-EXT, PFTs did not change; exercise endurance measured on the treadmill, cycle ergometer, arm ergometer, and by 6-min walk distance increased 40 +/- 8%, 43 +/- 10%, 12 +/- 5%, and 34 +/- 9%, respectively (p < 0.05); quadriceps strength increased 21 +/- 5% (p < 0.01); MIP and MEP increased 29 +/- 11% and 27 +/- 11%, respectively (p < 0.05); V(LIM) increased almost threefold (p < 0.05). At isotime near end-exercise, B, LE, carbon dioxide production (VCO2), oxygen consumption (VO2), ventilation, and breathing frequency (F) all fell after EXT (p < 0.05): deltaB correlated with deltaF (r = 0.58, p < 0.01). Increased MIP and V(LIM) did not correlate with improved breathlessness or exercise endurance. Similarly, changes in quadriceps strength and endurance did not correlate with changes in LE or exercise endurance. In conclusion, general nonspecific EXT improved ventilatory and peripheral muscle function in severe CAL, but such improvements did not appear to contribute significantly to reduced exertional symptoms and enhanced exercise performance.
Accelerated atherosclerosis in patients with diabetes is a major cause of their morbidity and mortality, and it is unresponsive to therapy aimed at restoring relative euglycemia. In hyperglycemia, nonenzymatic glycation and oxidation of proteins and lipids results in the accumulation of irreversibly formed advanced glycation endproducts. These advanced glycation endproducts engage their receptor in cells of the blood vessel wall, thereby activating mechanisms linked to the development of vascular lesions. We report here a model of accelerated and advanced atherosclerosis in diabetic mice deficient for apolipoprotein E. Treatment of these mice with the soluble extracellular domain of the receptor for advanced glycation endproducts completely suppressed diabetic atherosclerosis in a glycemia- and lipid-independent manner. These findings indicate interaction between the advanced glycation endproducts and their receptor is involved in the development of accelerated atherosclerosis in diabetes, and identify this receptor as a new therapeutic target in diabetic macrovascular disease.
In this study, we examined the fiber-type proportions, cross-sectional areas (CSA), and capillarization from needle biopsies of the vastus lateralis muscle in 20 patients with chronic obstructive pulmonary disease (COPD) (FEV1 = 37 +/- 11% predicted, peak VO2 = 13 +/- 4 mL.min-1.kg-1) and nine age-matched normal subjects (peak VO2 = 33 +/- 7 mL.min-1.kg-1). The effects of endurance training on these parameters were also evaluated in 11 of the 20 patients with COPD.
The proportion of Type I fiber was smaller in COPD than normals (34 +/- 14% vs 58 +/- 16 in normals, P < 0.0005) with a corresponding increase in Type IIb fiber (P = 0.015). The CSA of Type I, IIa, and IIab fibers was also smaller in COPD. The capillary to fiber ratio tended to be reduced in patients, but this difference did not reach statistical significance (P = 0.15). The number of capillary contact for Type I, IIa, and IIab fibers was significantly reduced in COPD compared with normal subjects (P < 0.05). When corrected for the CSA, this parameter was similar for both groups. After training, peak VO2 increased by 11% (P < 0.05), the fiber-type proportion remained unchanged, and the CSA of Type I and IIa fibers increased by 31 and 21%, respectively (P < 0.05). Although the number of capillary contact for each fiber types increased with training, the capillary to fiber ratio and the number of capillary contact for the different fiber types relative to their CSA remain unchanged.
We conclude that in COPD, 1) the vastus lateralis muscle is characterized by a marked decrease in Type I fiber proportion, an increase in Type IIb fiber proportion, a decrease in Type I, IIa, and IIab fiber CSA and by a relatively preserved capillarization; and 2) a 12-wk training program induces a significant increase in Type I and IIa CSA.
Changes in lung hyperinflation, dyspnea, and exercise endurance are important outcomes in assessing therapeutic responses in chronic obstructive pulmonary disease (COPD). Therefore, we studied the reproducibility of Borg dyspnea ratings, inspiratory capacity (IC; to monitor lung hyperinflation), and endurance time during constant-load symptom-limited cycle exercise in 29 patients with COPD (FEV1 = 40 +/- 2% predicted; mean +/- SEM). Responsiveness was also studied by determining the acute effects of nebulized 500 micrograms ipratropium bromide (IB) or saline placebo (P) on these measurements. During each of four visits conducted over an 8-wk period, spirometry and exercise testing were performed before and 1 h after receiving IB or P (randomized, double-blinded). Highly reproducible measurements included: endurance time (intraclass correlation R = 0.77, p < 0.0001); Borg ratings and IC at rest, at a standardized exercise time (STD), and at peak exercise (R > 0.6, p < 0.0001); and slopes of Borg ratings over time, oxygen consumption (V O2), and ventilation (R > 0.6, p < 0.0001). Responsiveness was confirmed by finding a significant drug effect for: change (Delta) in endurance time (p = 0.0001); DeltaBorgSTD and DeltaBorg-time slopes (p < 0.05); and DeltaIC at rest, at STD, and at peak exercise (p = 0.0001). With all completed visits, DeltaBorgSTD correlated better with DeltaICSTD than any other resting or exercise parameter (n = 115, r = -0.35, p < 0.001). We concluded that Borg dyspnea ratings, and measurements of IC and endurance time during submaximal cycle exercise testing are highly reproducible and responsive to change in severe COPD.
The purpose of this study was to evaluate whether strength training is a useful addition to aerobic training in patients with chronic obstructive pulmonary disease (COPD). Forty-five patients with moderate to severe COPD were randomized to 12 wk of aerobic training alone (AERO) or combined with strength training (AERO + ST). The AERO regimen consisted of three weekly 30-min exercise sessions on a calibrated ergocycle, and the ST regimen included three series of eight to 10 repetitions of four weight lifting exercises. Measurements of peripheral muscle strength, thigh muscle cross-sectional area (MCSA) by computed tomographic scanning, maximal exercise capacity, 6-min walking distance (6MWD), and quality of life with the chronic respiratory questionnaire were obtained at baseline and after training. Thirty-six patients completed the program and constituted the study group. The strength of the quadriceps femoris increased significantly in both groups (p < 0.05), but the improvement was greater in the AERO + ST group (20 +/- 12% versus 8 +/- 10% [mean +/- SD] in the AERO group, p < 0.005). The thigh MCSA and strength of the pectoralis major muscle increased in the AERO + ST group by 8 +/- 13% and 15 +/- 9%, respectively (p < 0.001), but not in the AERO group (3 +/- 6% and 2 +/- 10%, respectively, p > 0.05). These changes were significantly different in the two study groups (p < 0.01). The increase in strength of the latissimus dorsi muscle after training was modest and of similar magnitude for both groups. The changes in peak exercise work rate, 6MWD, and quality of life were comparable in the two groups. In conclusion, the addition of strength training to aerobic training in patients with COPD is associated with significantly greater increases in muscle strength and mass, but does not provide additional improvement in exercise capacity or quality of life.
Physiologic adaptations after an 8-wk endurance training program were examined in 13 patients with chronic obstructive pulmonary disease (COPD) (age, 64 +/- 4 [SD] yr; FEV1, 43 +/- 9% pred; PaO2, 72 +/- 8 mm Hg; and PaCO2, 36 +/- 2 mm Hg) and in eight healthy sedentary control subjects (61 +/- 4 yr). Both pre- and post-training studies included: (1) whole-body oxygen consumption (V O2) and one-leg O2 uptake (V O2leg) during exercise; and (2) intracellular pH (pHi) and inorganic phosphate to phosphocreatine ratio ([Pi]/[PCr]) during exercise; and half-time of [PCr] recovery. After training, the two groups increased peak V O2 (p < 0.05 each) and showed a similar fall in submaximal femoral venous lactate levels (p < 0.05 each). However, control subjects increased peak V E (p < 0.01) and raised peak O2 delivery (p = 0.05), not shown in patients with COPD. Both groups increased post-training O2 extraction ratio (p < 0.05). The most consistent finding, however, was in patients with COPD, who had a substantial improvement in cellular bioenergetics: (1) half-time of [PCr] recovery fell from 50 +/- 8 to 34 +/- 7 s (p = 0.02); and (2) at a given submaximal work rate, [Pi]/[PCr] ratio decreased and pHi increased (p < 0.05 each). We conclude that beneficial effects of training in patients with COPD essentially occurred at muscle level during submaximal exercise.
Mitochondrial number and function are altered in response to external stimuli in eukaryotes. While several transcription/replication factors directly regulate mitochondrial genes, the coordination of these factors into a program responsive to the environment is not understood. We show here that PGC-1, a cold-inducible coactivator of nuclear receptors, stimulates mitochondrial biogenesis and respiration in muscle cells through an induction of uncoupling protein 2 (UCP-2) and through regulation of the nuclear respiratory factors (NRFs). PGC-1 stimulates a powerful induction of NRF-1 and NRF-2 gene expression; in addition, PGC-1 binds to and coactivates the transcriptional function of NRF-1 on the promoter for mitochondrial transcription factor A (mtTFA), a direct regulator of mitochondrial DNA replication/transcription. These data elucidate a pathway that directly links external physiological stimuli to the regulation of mitochondrial biogenesis and function.